Abstract
Tumors develop gradually as a result of a multistep acquisition of genetic alterations where cells ultimately emerge as selfish, intruding, and metastatic cells. The genetic defects associated with the process of tumor progression affect control of proliferation, programmed cell death (or apoptosis), cell-aging, angiogenesis, escape from immune response, and invasion and metastasis (1). These characteristics of tumor cells are to be considered as interactive control boxes that are well taken care of in normal cells, but in which one or more failures have occurred during tumor development. The multistep nature of tumor development is evident from pathological examination of various tumor progression systems, indicating a continuous morphological progression from normal cells to premalignant stages to invasive tumors. The multistep process in tumorigenesis is responsible for the age-dependent appearance of tumors in humans; four to seven major genetic alterations that accumulate over time are responsible for the development of the ultimate tumor cell.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70.
Pardee AB. GI events and regulation of cell proliferation. Science 1989;246:603–608.
Jackman MR, Pines JN. Cyclins and the G2/M transition. Cancer Sury 1997;29:47–73.
Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Ann Rev Cell Dev Biol 1997;13:261–291.
Sherr CJ. D-type cyclins. TIBS 1995;20:187–190.
Altucci L, Addeo R, Cicatiello L, Dauvois S, Parker MG, Truss M, et al. 17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and pl05Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells. Oncogene 1996;12:2315–2324.
Brown JR, Nigh E, Lee RJ, Ye H, Thompson MA, Saudou F, et al. Fos family members induce cell cycle entry by activating cyclin Dl. Mol Cell Biol 1998;18:5609–5619.
Herber B, Truss M, Beato M, Muller R. Inducible regulatory elements in the human cyclin D1 promoter. Oncogene 1994;9:2105–2107.
Hunter T. Oncoprotein networks. Cell 1997;88:333–346.
Lukas J, Bartkova J, Bartek J. Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent kinase-pRb-controlled G1 checkpoint. Mol Cell Biol 1996;16:6917–6925.
Roussel MF. Key effectors of signal transduction and G1 progression. Adv Cancer Res 1998;74:1–24.
Watanabe G, Albanese C, Lee RJ, Reutens A, Vairo G, Henglein B, Pestell RG. Inhibition of cyclin D1 kinase activity is associated with E2F-mediated inhibition of cyclin D1 promoter activity through E2F and Spl. Mol Cell Biol 1998;18:3212–3222.
Assoian RK. Anchorage-dependent cell cycle progression. J Cell Biol 1997;136:1–4.
Bottazzi ME, Assoian RK. The extracellular matrix and mitogenic growth factors control G1 phase cyclins and cyclin-dependent kinase inhibitors. Trends Cell Biol 1997;7:348–352.
Schlaepfer DD, Hanks SK, Hunter T, van der Geer P. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 1994;372:786–791.
St.Croix B, Sheehan CE, Rak JW, Florenes VA, Slingerland JM, Kerbel RS. E-Cadherindependent growth suppression is mediated by the cyclin-dependent kinase inhibitor p27x1r1. J Cell Biol 1998;142:557–571.
Arber N, Doki Y, Han EK, Sgambato A, Zhou P, Kim NH, et al. Antisense to cyclin D1 inhibits the growth and tumorigenicity of human colon cancer cells. Cancer Res 1997; 57:1569–1574.
Lukas J, Bartkov J, Rohde M, Strauss M, Bartek J. Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity. Mol Cell Biol 1995;15:2600–2611.
Quelle DE, Ashmun RA, Shurtleff SA, Kato JY, Bar-Sagi D, Roussel MF, Sherr CJ. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev 1993;7:1559–1571.
Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995;81:323–330.
Beijersbergen RL, Carlee L, Kerkhoven RM, Bernards R. Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes. Genes Dev 1995;9:1340–1353.
Heifer RE, Sah VP, Williams BO, Makel TP, Weinberg RA, Jacks T. Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts. Mol Cell Biol 1996;16:2402–2407.
Muller H, Lukas J, Schneider A, Warthoe P, Bartek J, Eilers M, Strauss M. Cyclin D1 expression is regulated by the retinoblastoma protein. Proc Natl Acad Sci USA 1994;91:2945–2949.
Ohtani K, DeGregori J, Nevins JR. Regulation of the cyclin E gene by transcription factor E2F1. Proc Natl Acad Sci USA 1995;92:12146–12150.
Schulze A, Zerfass K, Spitkovsky D, Middendorp S, Berges J, Helin K, et al. Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Proc Natl Acad Sci USA 1995;92:11264–11268.
Kitagaw M, Higashi H, Jung HK, Suzuki-Takahashi I, Iked M, Tamai K, et al. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. EMBO J 1996;15:7060–7069.
Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M. Humancyclin E, a nuclear protein essential for the G 1-to-S phase transition. Mol Cell Biol 1995;15:2612–2624.
Resnitzky D, Reed SI. Different roles for cyclin D1 and E in regulation of the G1-to-S transition. Mol Cell Biol 1995;15:3463–3469.
Bernards R. E2F: a nodal point in cell cycle regulation. Biochim Biophys Acta 1997;1333: M33–M40.
Hurford RK Jr, Cobrinik D, Lee MH, Dyson N. pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Genes Dev 1997;11: 1447–1463.
Moberg K, Starz MA, Lees JA. E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry. Mol Cell Biol 1996;16:1436–1449.
Connell-Crowley L, Elledge SJ, Harper JW. Gl cyclin-dependent kinases are sufficient to initiate DNA synthesis in quiescent human fibroblasts. Curr Biol 1998;8:65–68.
Johnson DG, Schwarz JK, Cress WD, Nevins JR. Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 1993;365:349–352.
Yan Z, DeGregori J, Shohet R, Leone G, Stillman B, Nevins JR, Williams RS. Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells. Proc Natl Acad Sci USA 1998;95:3603–3608.
Romanowski P, Madine MA. Mechanisms restricting DNA replication to once per cell cycle: the role of Cdc6p and ORC. Trends Cell Biol 1997;7:9–10.
Guadagno TM, Newport JW. Cdk2 kinase is required for entry into mitosis as a positive regulator of Cdc2-cyclin B kinase activity. Cell 1996;84:73–82.
Krek W, Xu G, Livingston DM. Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint. Cell 1995;83:1149–1158.
Hunter T, Pines J. Cyclins and cancer II: Cyclin D and CDK inhibitors come of age. Cell 1994;79:573–582.
Diehl JA, Sherr CJ. A dominant-negative cyclin D1 mutant prevents nuclear import of cyclindependent kinase 4 (CDK4) and its phosphorylation by CDK-activating kinase. Mol Cell Biol 1997;17:7362–7374.
Hoyt MA. Eliminating all obstacles: regulated proteolysis in the eukaryotic cell cycle. Cell 1997;91:149–151.
Won KA, Reed SI. Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin. EMBO J 1996;15:4182–4193.
Elledge SJ, Winston J, Harper JW. A question of balance: the role of cyclin-kinase inhibitors in development and tumorigenesis. Trends Cell Biol 1996;6:388–392.
Harper JW. Cyclin dependent kinase inhibitors. Cancer Sury 1997;29:91–107.
Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 1995;9:1149–1163.
Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, et al. Identification of CDK4 sequences involved in cyclin D1 and p16 binding. J Biol Chem 1997;272:18869–18874.
Sherr CJ. G1 phase progression: cycling on cue. Cell 1994;79:551–555.
Sherr CJ. Cancer cell cycles. Science 1996;274:1672–1677.
Blain SW, Montalvo E, Massague J. Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27KiP1 with cyclin A-Cdk2 and cyclin D2-Cdk4. J Biol Chem 1997; 272:25863–25872.
Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai LH, Zhang P, et al. Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell 1995;6:387–400.
LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev 1997;11:847–862.
Sandhu C, Garbe J, Bhattacharya N, Daksis J, Pan CH, Yaswen P, et al. Transforming growth factor beta stabilizes pl 5 INK4B protein, increases p 15INK4B-cdk4 complexes, and inhibits cyclin Dl-cdk4 association in human mammary epithelial cells. Mol Cell Biol 1997;17:2458–2467.
Planas-Silva MD, Weinberg RA. Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Mol Cell Biol 1997;17:4059–4069.
Prall OWJ, Sarcevic B, Musgrove EA, Watts CKW, Sutherland RL. Estrogen-induced activation of Cdk4 and Cdk2 during Gl-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem 1997;272:10882–10894.
Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivieres S, Mercep L, Ferrari S. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem 1998;273:14424–14429.
Dulic V, Stein GH, Farahi Far D, Reed SI. Nuclear accumulation of p21c’P1 at the onset of mitosis: a role at the G2/M-phase transition. Mol Cell Biol 1998;18:546–557.
Niculescu AB, Chen X, Smeets M, Hengst L, Prives C, Reed SI. Effects of p21(Cip 1/Waf 1) at both the Gl/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol Cell Biol 1998;18:629–643.
Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997;88:323–331.
O’Connor PM. Mammalian Gl and G2 phase checkpoints. Cancer Sury 1997;29:151–182.
Zwijssen RM, Klompmakers R, Wientjes EB, Kristel PM, van den Burg B, Michalides RJ. Cyclin D1 triggers autonomous growth of breast cancer cells by governing cell cycle exit. Mol Cell Biol 1996;16:2554–2560.
Michalides R. Cell cycle regulators: mechanisms and their role in aetiology, prognosis, and treatment of cancer. J Clin Pathol 1999;52:555–568.
Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res 1996;68:67–108.
Hosokawa Y, Suzuki R, Joh T, Maeda Y, Nakamura S, Kodera Y, Arnold A, Seto M. A small deletion in the 3’-untranslated region of the cyclin D1/PRAD1/bcl-1 oncogene in a patient with chronic lymphocytic leukemia. Int J Cancer 1998;76:791–796.
Betticher DC, Thatcher N, Altenmatt HJ, Hoban P, Ryder WD, Heighway J. Alternate splicing produces a novel cyclin D1 transcript. Oncogene 1995;11:1005–1011.
Sawa H, Ohshima TA, Ukita H, Murakami H, Chiba Y, Kamada H, et al. Alternatively spliced forms of cyclin Dl modulate entry into the cell cycle in an inverse manner. Oncogene 1998;16:1701–1712.
He J, Allen JR, Collins VP, Allalunis-Turner MJ, Godbout R, Day RS, James CD. CDK4 amplification is an alternative mechanism to p16 gene homozygous deletion in glioma cell lines. Cancer Res 1994;54:5804–5807.
Schmidt EE, Ichimura K, Reifenberger G, Collins VP. CDKN2 (p16/MTS 1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res 1994;54: 6321–6324.
Tsao H, Benoit E, Sober AJ, Thiele C, Haluska FG. Novel mutations in the p16/CDKN2A binding region of the cyclin-dependent kinase-4 gene. Cancer Res 1998;58:109–113.
Bartek J, Bartkova J, Lukas J. The retinoblastoma protein pathway and the restriction point. Curr Opin Cell Biol 1996;8:805–814.
Snijders PJF, van Duin M, Walboomers JMM, Steenbergen RDM, Risse EKJ, Helmerhorst TJM, et al. Telomerase activity exclusively in cervical carcinomas and a subset of cervical intraepithelial neoplasia grade III lesions: strong association with elevated messenger RNA levels of its catalytic subunit and high-risk human papillomavirus DNA. Cancer Res 1998;58:3812–3818.
Tang R, Cheng A-J, Wang J-Y, Wang TC. Close correlation between telomerase expression and adenomatous polyp progression in multistep colorectal carcinogenesis. Cancer Res 1998;58:4052–4054.
Alevizopoulos K, Vlach J, Hennecke S, Amati B. Cyclin E and c-Myc promote cell proliferation in the presence of p161NK4a and of hypophosphorylated retinoblastoma family proteins. EMBO J 1997;16:5322–5333.
Sofer-Levi Y, Resnitzky D. Apoptosis induced by ectopic expression of cyclin D1 but not cyclin E. Oncogene 1996;13:2431–2437.
Hinds PW, Dowdy SF, Eaton EN, Arnold A, Weinberg RA. Function of a human cyclin gene as an oncogene. Proc Natl Acad Sci USA 1994;91:709–713.
Mueller A, Odze R, Jenkins TD, Shahsesfaei A, Nakagawa H, Inomoto T, Rustgi AK. A transgenic mouse model with cyclin D1 overexpression results in cell cycle, epidermal growth factor receptor and p53 abnormalities. Cancer Res 1997;57:5542–5549.
Lovec H, Grzeschiczek A, Kowalski MB, Moroy T. Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J 1994;13: 3487–3495.
Robles AI, Larcher F, Whalin RB, Murillas R, Richie E, Gimenez-Conti IB, et al. Expression of cyclin D1 in epithelial tissues of transgenic mice results in epidermal hyperproliferation and severe thymic hyperplasia. Proc Natl Acad Sci USA 1996;93:7634–7638.
Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 1994;369:669–671.
Bortner DM, Rosenberg MP. Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol Cell Biol 1997;17:453–459.
Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, et al. Cyclin DI provides a link between development and oncogenesis in the retina and breast. Cell 1995;82:621–630.
Fantl V, Stamp G, Andrews A, Rosewell I, Dickson C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dey 1995;9:2364–2372.
Zwijsen RM, Wientjens E, Klompmaker R, Van der Sman J, Bernards R, Michalides RJ. CDK-independent activation of estrogen receptor by cyclin Dl. Cell 1997;88:405–415.
Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, et al. Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Mol Cell Biol 1997;17: 5338–5347.
Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, et al. Cyclin D2 is an FSHresponsive gene involved in gonadal cell proliferation and oncogenesis. Nature 1996; 384:470–474.
Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA. Effects of an Rb mutation in the mouse. Nature 1992;359:295–300.
Zhou P, Jiang W, Weghorst CM, Weinstein IB. Overexpression of Cyclin D1 enhances gene amplification. Cancer Res 1996;56:36–39.
Shen CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G l -phase progression. Genes Dey 1999;13:1501–1502.
De Jong JS, Van Diest PJ, Michalides RJAM, Baak JPA. Concerted expression of the genes coding for p21 and cyclin D1 is associated with growth inhibition and differentiation in various carcinomas. Mol Pathol 1999;52:78–83.
De Boer CJ, van Krieken JH, Schuuring E, Kluin PM. Bc1–1/cyclin D1 in malignant lymphoma. Ann Oncol 1997;8:109–117.
Dillon DA, Howe CL, Bosari S, Costa J. The molecular biology of breast cancer: accelerating clinical applications. Crit Rev Oncog 1998;9:125–140.
Mowat MRA. p53 in tumor progression: life, death, and everything. Adv Cancer Res 1998;74:25–48.
Weber JD, Taylor LJ, Roussel MF, et al. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1999;1:20–26.
Coco Martin JM, Balkenende A, Verschoor T, Lallemand F, Michalides R. Cyclin D1 overexpression enhances radiation-induced apoptosis and radiosensitivity in a breast tumor cell line. Cancer Res 1999;59:1134–1140.
Yoo SS, Carter D, Turner BC, Sasaki CT, Son YH, Wilson LD, et al. Prognostic significance of cyclin D1 protein levels in early-stage larynx cancer treated with primary radiation. Iin J Cancer 2000;90:22–28.
McGill G, Fisher DE. p53 and cancer therapy: a double-edged sword. J Clin Inv 1999;104:223–224.
Banerjee D, Schnieders B, Fu JZ, Adhikari D, Zhao SC, Bertino JR. Role of E2F-1 in chemosensitivity. Cancer Res 1998;58:4292–4296.
Fearon ER. Human cancer syndromes: clues to the origin and nature of cancer. Science 1997;278:1043–1050.
Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 1996;56:2488–2492.
Michalides R. Deregulation of cyclin D1 in cancer, in The Biology of Tumors (Mihich E, Croce C, eds.), Plenum Press, New York, 1998, pp. 127–145.
Buerger H, Otterbach F, Simon R, Poremba C, Diallo R, Decker T, et al. Comparative genomic hybridization of ductal carcinoma in situ of the breast-evidence of multiple genetic pathways. J Pathol 1999a;187:396–402.
Buerger H, Otterbach F, Simon R, Schafer KL, Poremba C, Diallo R, et al. Different genetic pathways in the evolution of invasive breast cancer are associated with distinct morphological subtypes. J Pathol 1999b;189:521–526.
Buerger H, Simon R, Schafer KL, Diallo R, Littmann R, Poremba C, et al. Genetic relation of lobular carcinoma in situ, ductal carcinoma in situ, and associated invasive carcinoma of the breast. Mol Pathol 2000;53:118–121.
Dosaka-Akita H, Hu SX, Fujino M, Harada M, Kinoshita I, Xu HJ, et al. Altered retinoblastoma protein expression in nonsmall cell lung cancer: its synergistic effects with altered ras and p53 protein status on prognosis. Cancer 1997;79:1329–1337.
Yoo GH, Xu HJ, Brennan JA, Westra W, Hruban RH, Koch W, et al. Infrequent inactivation of the retinoblastoma gene despite frequent loss of chromosome 13q in head and neck squamous cell carcinoma. Cancer Res 1994;54:4603–4606.
Olshan AF, Weissler MC, Pei H, Conway K, Anderson S, Fried DB, Yarbrough WG. Alterations of the p16 gene in head and neck cancer: frequency and association with p53, PRAD1 and HPV. Oncogene 1997;14:811–818.
Aaltomaa S, Eskelinen M, Lipponen P. Expression of cyclin A and D proteins in prostate cancer and their relation to clinopathological variables and patient survival. Prostate 1999;38:175–182.
Ito Y, Takeda T, Sakon M, Monden M, Tsujimoto M, Matsuura N. Expression and prognostic role of cyclin-dependent kinase 1 (cdc2) in hepatocellular carcinoma. Oncology 2000;59:68–74.
Wolowiec D, Berger F, Ffrench P, Bryon PA, Ffrench M. CDK 1 and cyclin A expression is linked to cell proliferation and associated with prognosis in non-Hodgkin’s lymphomas. Leuk Lymphoma 1999;35:147–157.
Van Diest PJ, Brugal G, Baak JPA. Proliferation markers in tumours: interpretation and clinical value. J Clin Pathol 1998;51:716–724.
Noguchi T, Dobashi Y, Minehara H, Itoman M, Kameya T. Involvement of cyclins in cell proliferation and their clinical implications in soft tissue smooth muscle tumors. Am J Pathol 2000;156:2135–2147.
Handa K, Yamakawa M, Takeda H, Kimura S, Takahashi T. Expression of cell cycle markers in colorectal carcinoma: superiority of cyclin A as an indicator of poor prognosis. Int J Cancer 1999;84:225–233.
Aaltomaa S, Lipponen P, Eskelinen M, Ala-Opas M, Kosma VM. Prognostic value and expression of p21(wafl/cipl) protein in prostate cancer. Prostate 1999;39:8–15.
Kallakury BV, Sheehan CE, Rhee SJ, Fisher HA, Kaufman RP Jr, Rifkin MD, Ross JS. The prognostic significance of proliferation-associated nucleolar protein p 120 expression in prostate adenocarcinoma: a comparison with cyclins A and B 1, Ki-67, proliferating cell nuclear antigen, and p34cdc2. Cancer 1999;85:1569–1576.
Brien TP, Depowski PL, Sheehan CE, Ross JS, McKenna BJ. Prognostic factors in gastric cancer. Mod Pathol 1998;11:870–877.
Furihata M, Ishikawa T, Inoue A, Yoshikawa C, Sonobe H, Ohtsuki Y, et al. Determination of the prognostic significance of unscheduled cyclin A overexpression in patients with esophageal squamous cell carcinoma. Clin Cancer Res 1996;2:1781–1785.
Yasunaga M, Tabira Y, Kondo K, Okuma T, Kitamura N. The prognostic significance of cell cycle markers in esophageal cancer after neoadjuvant chemotherapy. Dis Esophagus 1999;12:120–127.
Dobashi Y, Shoji M, Jiang SX, Kobayashi M, Kawakubo Y, Kameya T. Active cyclin A-CDK2 complex, a possible critical factor for cell proliferation in human primary lung carcinomas. Am J Pathol 1998;153:963–972.
Volm M, Koomagi R. Relevance of proliferative and pro-apoptotic factors in non-small-cell lung cancer for patient survival. Br J Cancer 2000;82:1747–1754.
Volm M, Koomagi R, Rittgen W. Clinical implications of cyclins, cyclin-dependent kinases, RB and E2F1 in squamous-cell lung carcinoma. Int J Cancer 1998;79:294–299.
Volm M, Rittgen W, Drings P. Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas. Br J Cancer 1998;77:663–669. Published erratum Br J Cancer 1998;77:1198.
Furihata M, Ohtsuki Y, Sonobe H, Shuin T, Yamamoto A, Terao N, Kuwahara M. Cyclin A overexpression in carcinoma of the renal pelvis and ureter including dysplasia: immunohistochemical findings in relation to prognosis. Clin Cancer Res 1997;3:1399–1404.
Molendini L, Benassi MS, Magagnoli G, Merli M, Sollazzo MR, Ragazzini P, et al. Prognostic significance of cyclin expression in human osteosarcoma. Int J Oncol 1998;12:1007–1011.
Huuhtanen RL, Blomqvist CP, Bohling TO, Wiklund TA, Tukiainen EJ, Virolainen M, et al. Expression of cyclin A in soft tissue sarcomas correlates with tumor aggressiveness. Cancer Res 1999;59:2885–2890.
Huuhtanen RL, Wiklund TA, Blomqvist CP, Bohling TO, Virolainen MJ, Tribukait B, Andersson LC. A high proliferation rate measured by cyclin A predicts a favourable chemotherapy response in soft tissue sarcoma patients. Br J Cancer 1999;81:1017–1021.
Kim SH, Lewis JJ, Brennan MF, Woodruff JM, Dudas M, Cordon-Cardo C. Overexpression of cyclin D 1 is associated with poor prognosis in extremity soft-tissue sarcomas. Clin Cancer Res 1998;4:2377–2382.
Megha T, Lazzi S, Ferrari F, Vatti R, Howard CM, Cevenini G, et al. Expression of the G2-M checkpoint regulators cyclin Bl and P34CDC2 in breast cancer: a correlation with cellular kinetics. Anticancer Res 1999;19:163–169.
Murakami H, Furihata M, Ohtsuki Y, Ogoshi S. Determination of the prognostic significance of cyclin B1 overexpression in patients with esophageal squamous cell carcinoma. Virchows Arch 1999;434:153–158.
Suhardja AS, Kovacs KT, Rutka JT. Molecular pathogenesis of pituitary adenomas: a review. Acta Neurochir (Wien) 1999;141:729–736.
Kudoh S, Kumaravel TS, Kuramavel B, Eguchi M, Asaoku H, Dohy H, et al. Protein expression of cell cycle regulator, p27Kip1, correlates with histopathological grade of non-Hodgkin’s lymphoma. Jpn J Cancer Res 1999;90:1262–1269.
Yatabe Y, Nakamura S, Seto M, Kuroda H, Kagami Y, Suzuki R, et al. Clinicopathologic study of PRAD1/cyclin D1 overexpressing lymphoma with special reference to mantle cell lymphoma. A distinct molecular pathologic entity. Am J Surg Pathol 1996;20:1110–1122.
Swerdlow SH, Yang WI, Zukerberg LR, Harris NL, Arnold A, Williams ME. Expression of cyclin D1 protein in centrocytic/mantle cell lymphomas with and without rearrangement of the BCL1/cyclin D1 gene. Hum Pathol 1995;26:999–1004.
Yatabe Y, Suzuki R, Tobinai K, Matsuno Y, Ichinohasama R, Okamoto M, et al. Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D l-positive MCL and cyclin DI- negati v e MCL-like B-cell lymphoma. Blood 2000;95:2253–2261.
Gillett CE, Lee AH, Millis RR, Barnes DM. Cyclin D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. J Pathol 1998;184:396–400.
Mommers ECM, Van Diest PJ, Leonhart AM, Meijer CJLM, Baak JPA. Expression of proliferation and apoptosis related proteins in usual ductal hyperplasia of the breast. Hum Pathol 1998;29:1539–1545.
Weinstat-Saslow D, Merino MJ, Manrow RE, Lawrence JA, Bluth RF, Wittenbel KD, et al. Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions. Nat Med 1995;1:1257–1260.
Simpson JF, Quan DE, O’Malley F, Odom-Maryon T, Clarke PE. Amplification of CCND1 and expression of its protein product, cyclin D1, in ductal carcinoma in situ of the breast. Am J Pathol 1997;151:161–168.
Oyama T, Kashiwabara K, Yoshimoto K, Arnold A, Koerner FC. Frequent overexpression of the cyclin D1 oncogene in invasive lobular carcinoma of the breast. Cancer Res 1998;58:2876–2880.
Michalides R, Hageman PH, van Tinteren H, Houben L, Wientjens E, Klompmaker R, Peterse J. A clinico-pathological study on overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast cancer. Br J Cancer 1996;73:728–734.
Van Diest PJ, Van Dam P, Henzen-Logmans SC, Berns E, Van der Burg MEL, Green J, Vergote I. A scoring system for immunohistochemical staining: consensus report of the task force for basic research of the EORTC-GCCG. J Clin Pathol 1997a;50:801–804.
Seshadri R, Lee CS, Hui R, McCaul K, Horsfall DJ, Sutherland RL. Cyclin D1 amplification is not associated with reduced overall survival in primary breast cancer but may predict early relapse in patients with features of good prognosis. Clin Canc Res 1996;2:1177–1184.
Courjal F, Louason G, Speiser P, Katsaros D, Zeillinger R, Theillet C. Cyclin gene amplification and overexpression in breast and ovarian cancers: evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors. Int J Cancer 1996;69:247–253.
Cuny M, Kramar A, Courjal F, Johannsdottir V, Iacopetta B, Fontaine H, et al. Relating genotype and phenotype in breast cancer: an analysis of the prognostic significance of amplification at eight different genes or loci and of p53 mutations. Cancer Res 2000;60: 1077–1083.
Tsuda H, Hirohashi S, Shimosato Y, Hirota T, Tsugane S, Yamamoto H, et al. Correlation between long-term survival in breast cancer patients and amplification of two putative oncogene-coamplification units: hst-1/int-2 and c-erbB-2/ear-1. Cancer Res 1989;49:3104–3108.
Schuuring E, Verhoeven E, Tinteren H. van, Peterse JL, Nunnink B, Thunnissen FBJM, et al. Amplification of genes within the chromosome 11q13 region is indicative of poor prognosis in patients with operable breast cancer. Cancer Res 1992;52:5229–5234.
An HX, Beckmann MW, Reifenberger G, Bender HG, Niederacher D. Gene amplification and overexpression of CDK4 in sporadic breast carcinomas is associated with high tumor cell proliferation. Am J Pathol 1999;154:113–118.
Nielsen NH, Emdin SO, Cajander J, Landberg G. Deregulation of cyclin E D1 in breast cancer is associated with inactivation of the retinoblastoma protein. Oncogene 1997;14:295–304.
Reed W, Fllrenes VA, Holm R, Hannisdal E, Nesland JM. Elevated levels of p27, p21 and cyclin DI correlate with positive oestrogen and progesterone receptor status in node-negative breast carcinoma patients. Virchows Arch 1999;435:116–124.
Kenny FS, Hui R, Musgrove EA, Gee JM, Blarney RW, Nicholson RI, et al. Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer. Clin Cancer Res 1999;5:2069–2076.
Utsumi T, Yoshimura N, Maruta M, Takeuchi S, Ando J, Mizoguchi Y, Harada N. Correlation of cyclin Dl MRNA levels with clinico-pathological parameters and clinical outcome in human breast carcinomas. Int J Cancer 2000;89:39–43.
Hui R, Cornish AL, McClelland RA, Robertson JF, Blamey RW, Musgrove EA, et al. Cyclin D1 and estrogen receptor messenger RNA levels are positively correlated in primary breast cancer. Clin Canc Res 1996;2:923–928.
Pelosio P, Barbareschi M, Bonoldi E, Marchetti A, Verderio P, Caffo O, et al. Clinical significance of cyclin DI expression in patients with node-positive breast carcinoma treated with adjuvant therapy. Ann Oncol 1996;7:695–703.
Doki Y, Imoto M, Han EK, Sgambato A, Weinstein IB. Increased expression of the p27K1P1 protein in human esophageal cancer cell lines that over-express cyclin D 1. Carcinogenesis 1997;18:1139–1148.
Nadal A, Jares P, Cazorla M, Fernandez PL, Sanjuan X, Hernandez L, et al. p21wAF1/CIPI expression is associated with cell differentiation but not with p53 mutations in squamous cell carcinomas of the larynx. J Pathol 1997;183:156–163.
McIntosh GG, Anderson JJ, Milton I, Steward M, Parr AH, Thomas MD, et al. Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene 1995;11:885–891.
Maeda K, Chung YS, Kang SM, Ogawa M, Onoda N, Nakata B, et al. Overexpression of cyclin D1 and p53 associated with disease recurrence in colorectal adenocarcinoma. Int J Cancer 1997;74:310–315.
Sutter T, Doi S, Carnevale KA, Arber N, Weinstein IB. Expression of cyclin D1 and E in human colon adenocarcinomas. J Med 1997;28:285–309.
Bartkova J, Lukas J, Strauss M, Bartek J. The PRAD-1/cyclin D1 oncogene product accumulates aberrantly in a subset of colorectal carcinomas. Int J Cancer 1994;58:568–573.
Zhang T, Nanney LB, Luongo C, Lamps L, Heppner KJ, DuBois RN, Beauchamp RD. Concurrent overexpression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4) in intestinal adenomas from multiple intestinal neoplasia (Min) mice and human familial adenomatous polyposis patients. Cancer Res 1997;57:169–175.
Palmqvist R, Stenling R, Oberg A, Landberg G. Expression of cyclin D1 and retinoblastoma protein in colorectal cancer. Eur J Cancer 1998;34:1575–1581.
Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N, Beger HG. Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res 1997;57:1634–1637.
Gansauge F, Gan sauge S, Schmidt E, Muller J, Beger HG. Prognostic significance of molecular alterations in human pancreatic carcinoma: an immunohistological study. Langenbecks Arch Surg 1998;383:152–155.
Naka T, Kobayashi M, Ashida K, Toyota N, Kaneko T, Kaibara N. Aberrant p16mK4 expression related to clinical stage and prognosis in patients with pancreatic cancer. Int J Oncol 1998;12:1111–1116.
Kallakury BV, Sheehan CE, Ambros RA, Fisher HA, Kaufman RP, Ross JS. The prognostic significance of p34odo2 and cyclin D1 protein expression in prostate adenocarcinoma. Cancer 1997;80:753–763.
Hui AM, Cui X, Makuuchi M, Li X, Shi YZ, Takayama T. Decreased p27(Kip I) expression and cyclin D1 overexpression, alone and in combination, influence recurrence and survival of patients with resectable extrahepatic bile duct carcinoma. Hepatology 1999;30:1167–1173.
Ito Y, Matsuura N, Sakon M, Miyoshi E, Noda K, Takeda T, et al. Expression and prognostic roles of the Gl-S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence. Hepatology 1999;30:90–99.
Peng SY, Chou SP, Hsu HC. Association of downregulation of cyclin D1 and of overexpression of cyclin E with p53 mutation, high tumor grade and poor prognosis in hepatocellular carcinoma. J Hepatol 1998;29:281–289.
Blok P, Craanen ME, Van Diest PJ, Dekker WJ, Tytgat GN. Lack of cycl in DI overexpression in gastric carcinogenesis. Histopathol 2000;36:151–155.
Jang SJ, Park YW, Park MH, Lee JD, Lee YY, Jung TJ, et al. Expression of cell-cycle regulators, cyclin E and p21v’AFl I’i potential prognostic markers for gastric cancer. Eur J Surg Oncol 1999;25:157–163.
Muller W, Noguchi T, Wirtz HC, Hommel G, Gabbert HE. Expression of cell-cycle regulatory proteins cyclin D1, cyclin E, and their inhibitor p21 wAFI/CIPI in gastric cancer. J Pathol 1999;189:186–193.
Takano Y, Kato Y, van Diest PJ, Masuda M, Mitomi H, Okayasu I. Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases. Am J Pathol 2000;156:585–594.
Takano Y, Kato Y, Masuda M, Ohshima Y, Okayasu I. Cyclin D2, but not cyclin D1, overexpression closely correlates with gastric cancer progression and prognosis. J Pathol 1999;189:194–200.
Hedberg Y, Davoodi E, Roos G, Ljungberg B, Landberg G. Cyclin-D1 expression in human renal-cell carcinoma. Int J Cancer 1999;84:268–272.
Bringuier PP, Tamimi Y, Schuuring E, Schaliken J. Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification. Oncogene 1996; 12:1747–1753.
Niehans GA, Kratzke RA, Froberg MK, Aeppli DM, Nguyen PL, Geradts J. G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder. Br J Cancer 1999;80:1175–1184.
Shin KY, Kong G, Kim WS, Lee TY, Woo YN, Lee JD. Overexpression of cyclin D1 correlates with early recurrence in superficial bladder cancers. Br J Cancer 1997;75:1788–1792.
Wagner U, Suess K, Luginbuhl T, Schmid U, Ackermann D, Zellweger T, et al. Cyclin D1 overexpression lacks prognostic significance in superficial urinary bladder cancer. J Pathol 1999;188:44–50.
Diebold J, Mosinger K, Peiro G, Pannekamp U, Kaltz C, Baretton GB, Meier W, Lohrs U. 20g13 and cyclin D1 in ovarian carcinomas. Analysis by fluorescence in situ hybridization. J Pathol 2000;190:564–571.
Akervall JA, Michalides RJ, Mineta H, Balm A, Borg A, Dictor MR, et al. Amplification of cyclin D1 in squamous cell carcinoma of the head and neck and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression. Cancer 1997;79(2):380–389.
Nogueira CP, Dolan RW, Gooey J, Byahatti S, Vaughan CW, Fuleihan NS, et al. Inactivation of p53 and amplification of cyclin D1 correlate with clinical outcome in head and neck cancer. Laryngoscope 1998;108:345–350.
Kyomoto R, Kumazawa H, Toda Y, Sakaida N, Okamura A, Iwanaga M, et al. Cyclin-D1gene amplification is a more potent prognostic factor than its protein over-expression in human head-and-neck squamous-cell carcinoma. Int J Cancer 1997;74:576–581.
Michalides RJ, Van Veelen N, Hart A, Loftus B, Wientjens E, Balm A. Overexpression of cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Res 1995;55:975–978.
Michalides R, van Veelen N, Kristel P, Hart A, Loftus B, Hilgers F, Balm A. Overexpression of cyclin D1 indicates a poor prognosis in squamous cell carcinoma of the head and neck. Arch Oto Head Neck Surg 1997;123:497–502.
Pignataro L, Pruneri G, Carboni N, Capaccio P, Cesana BM, Neri A, Buffa R. Clinical relevance of cyclin D1 protein overexpression in laryngeal squamous cell carcinoma. J Clin Oncol 1998;16:3069–3077.
Pruneri G, Pignataro L, Carboni N, Buffa R, Di Finizio D, Cesana BM, Neri A. Clinical relevance of expression of the CIP/KIP cell-cycle inhibitors p21 and p27 in laryngeal cancer. J Clin Oncol 1999;17:3150–3159.
Bellacosa A, Almadori G, Cavallo S, Cadoni G, Galli J, Ferrandina G, et al. Cyclin D1 gene amplification in human laryngeal squamous cell carcinomas: prognostic significance and clinical implications. Clin Cancer Res 1996;2:175–180.
Anayama T, Furihata M, Ishikawa T, Ohtsuki Y, Ogoshi S. Positive correlation between p27x’Pl expression and progression of human esophageal squamous cell carcinoma. Int J Cancer 1998;79:439–443.
Gramlich TL, Fritsch CR, Maurer D, Eberle M, Gamier TS. Differential polymerase chain reaction assay of cyclin DI gene amplification in esophageal carcinoma. Diagn Mol Pathol 1994;3:255–259.
Ishikawa T, Furihata M, Ohtsuki Y, Murakami H, Inoue A, Ogoshi S. Cyclin D1 overexpression related to retinoblastoma protein expression as a prognostic marker in human oesophageal squamous cell carcinoma. Br J Cancer 1998;77:92–97.
Itami A, Shimada Y, Watanabe G, Imamura M. Prognostic value of p27(Kipl) and CyclinD 1 expression in esophageal cancer. Oncology 1999;57:311–317.
Kuwahara M, Hirai T, Yoshida K, Yamashita Y, Hihara J, Inoue H, Toge T. p53, p21(Waf 1/ Cipl) and cyclin D1 protein expression and prognosis in esophageal cancer. Dis Esophagus 1999;12:116–119.
Masuda M, Hirakawa N, Nakashima T, Kuratomi Y, Komiyama S. Cyclin DI overexpression in primary hypopharyngeal carcinomas. Cancer 1996;78:390–395.
Matsumoto M, Furihata M, Ishikawa T, Ohtsuki Y, Ogoshi S. Comparison of deregulated expression of cyclin D1 and cyclin E with that of cyclin-dependent kinase 4 (CDK4) and CDK2 in human oesophageal squamous cell carcinoma. Br J Cancer 1999;80:256–261.
Naitoh H, Shibata J, Kawaguchi A, Kodama M, Hattori T. Overexpression and localization of cyclin D1 mRNA and antigen in esophageal cancer. Am J Pathol 1995;146:1161–1169.
Nakagawa H, Zukerberg L, Togawa K, Meltzer SJ, Nishihara T, Rustgi AK. Human cyclin D1 oncogene and esophageal squamous cell carcinoma. Cancer 1995;76:541–549.
Sarbia M, Stahl M, Fink U, Heep H, Dutkowski P, Willers R, et al. Prognostic significance of cyclin D1 in esophageal squamous cell carcinoma patients treated with surgery alone or combined therapy modalities. Int J Cancer 1999;84:86–91.
Shimada Y, Imamura M, Watanabe G, Uchida S, Harada H, Makino T, Kano M. Prognostic factors of oesophageal squamous cell carcinoma from the perspective of molecular biology. Br J Cancer 1999;80:1281–1288.
Shinozaki H, Ozawa S, Ando N, Tsuruta H. Terada M, Ueda M, Kitajima M. Cyclin D1 amplification as a new predictive classification for squamous cell carcinoma of the esophagus, adding gene information. Clin Cancer Res 1996;2:1155–1161.
Takeuchi H, Ozawa S, Ando N, Shih CH, Koyanagi K, Ueda M, Kitajima M. Altered p16/ MTS 1/CDKN2 and cyclin D1/PRAD-1 gene expression is associated with the prognosis of squamous cell carcinoma of the esophagus. Clin Cancer Res 1997;3:2229–2236.
Samejima R, Kitajima Y, Yunotani S, Miyazaki K. Cyclin D1 is a possible predictor of sensitivity to chemoradiotherapy for esophageal squamous cell carcinoma. Anticancer Res 1999;19:5515–5521.
Hirai T, Kuwahara M, Yoshida K, Osaki A, Toge T. The prognostic significance of p53, p21 (Waf 1/Cip 1), and cyclin D1 protein expression in esophageal cancer patients. Anticancer Res 1999;19:4587–4591.
Ikeda G, Isaji S, Chandra B, Watanabe M, Kawarada Y. Prognostic significance of biologic factors in squamous cell carcinoma of the esophagus. Cancer 1999;86:1396–1405.
Mineta H, Miura K, Suzuki I, Takebayashi S, Misawa K, Ueda Y, Ichimura K. p27 expression correlates with prognosis in patients with hypopharyngeal cancer. Anticancer Res 1999; 19:4407–4412.
Nishimura G, Tsukuda M, Zhou LX, Furukawa S, Baba Y. Cyclin D1 expression as a prognostic factor in advanced hypopharyngeal carcinoma. J Laryngol Otol 1998;112:552–555.
Kuo MY, Lin CY, Hahn LJ, Cheng SJ, Chiang CP. Expression of cyclin D1 is correlated with poor prognosis in patients with areca quid chewing-related oral squamous cell carcinomas in Taiwan. J Oral Pathol Med 1999;28:165–169.
Wong RJ, Keel SB, Glynn RJ, Varvares MA. Histological pattern of mandibular invasion by oral squamous cell carcinoma. Laryngoscope 2000;110:65–72.
Caputi M, Groeger AM, Esposito V, Dean C, De Luca A, Pacilio C, et al. Prognostic role of cyclin D1 in lung cancer. Relationship to proliferating cell nuclear antigen. Am J Respir Cell Mol Biol 1999;20:746–750.
Keum JS, Kong G, Yang SC, Shin DH, Park SS, Lee JH, Lee JD. Cyclin D1 overexpression is an indicator of poor prognosis in resectable non-small cell lung cancer. Br J Cancer 1999;81:127–132.
Betticher DC, Heighway J, Hasleton PS, Altermatt HJ, Ryder WD, Cerny T, Thatcher N. Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected nonsmall-cell lung cancer. Br J Cancer 1996;73:294–300.
Nishio M, Koshikawa T, Yatabe Y, Kuroishi T, Suyama M, Nagatake M, et al. Prognostic significance of cyclin D1 and retinoblastoma expression in combination with p53 abnormalities in primary, resected non-small cell lung cancers. Clin Cancer Res 1997;3:1051–1058.
Brambilla E, Moro D, Gazzeri S, Brambilla C. Alterations of expression of Rb, p16(INK4A) and cyclin D1 in non-small cell lung carcinoma and their clinical significance. J Pathol 1999;188:351–360.
Kwa HB, Michalides RJ, Dijkman JH, Mooi WJ. The prognostic value of NCAM, p53 and cyclin D1 in resected non-small cell lung cancer. Lung Cancer 1996;14:207–217.
Yang WI, Chung KY, Shin DH, Kim YB. Cyclin D1 protein expression in lung cancer. Yonsei Med J 1996;37:142–150.
Sallinen SL, Sallinen PK, Kononen JT, Syrjakoski KM, Nupponen NN, Rantala IS, et al. Cyclin D1 expression in astrocytomas is associated with cell proliferation activity and patient prognosis. J Pathol 1999;188:289–293.
Volm M, Koomagi R, Stammler G, Rittgen W, Zintl F, Sauerbrey A. Prognostic implications of cyclins (D1, E, A), cyclin-dependent kinases (CDK2, CDK4) and tumor-suppressor genes (pRB, pl6ixx4A) in childhood acute lymphoblastic leukemia. Int J Cancer 1997;74:508–512.
Houldsworth J, Reuter V, Bosl GJ, Chaganti RS. Aberrant expression of cyclin D2 is an early event in human male germ cell tumorigenesis. Cell Growth Differ 1997;8:293–299.
Sauerbrey A, Hafer R, Zintl F, Volm M. Analysis of cyclin D1 in de novo and relapsed childhood acute lymphoblastic leukemia. Anticancer Res 1999;19:645–649.
Antonescu CR, Leung DH, Dudas M, Ladanyi M, Brennan M, Woodruff JM, Cordon-Cardo C. Alterations of cell cycle regulators in localized synovial sarcoma: A multifactorial study with prognostic implications. Am J Pathol 2000;156:977–983.
Scott KA, Walker RA. Lack of cyclin E immunoreactivity in non-malignant breast and association with proliferation in breast cancer. Br J Cancer 1997;76:1288–1292.
Keyomarsi K, O’Leary N, Molnar G, Lees E, Fingert HJ, Pardee AB. Cyclin E, a potential prognostic marker for breast cancer. Cancer Res 1994;54:380–385.
Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, et al. Decreased levels of the cell-cycle inhibitor p27K’P1 protein: prognostic implications in primary breast cancer. Nature Med 1997;3:227–230.
Tan P, Cady B, Wanner M, Worland P, Cukor B, Magi-Galluzzi C, et al. The cell cycle inhibitor p27 is an independent prognostic marker in small (Tla,b) invasive breast carcinomas. Cancer Res 1997;57:1259–1263.
Fredersdorf S, Burns J, Milne AM, Packham G, Fallis L, Gillett CE, et al. High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip 1) and degree of malignancy in human breast and colorectal cancers. Proc Natl Acad Sci USA 1997;94:6380–6385.
Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, et al. Expression of cell-cycle regulators p27KiPI and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 1997;3:222–225.
Nielsen NH, Arnerlov C, Emdin SO, Landberg G. Cyclin E overexpression, a negative prognostic factor in breast cancer with strong correlation to oestrogen receptor status. Br J Cancer 1996;74:874–880.
Nielsen NH, Arnerlov C, Cajander S, Landberg G. Cyclin E expression and proliferation in breast cancer. Anal Cell Pathol 1998;17:177–188.
Yasui W, Kudo Y, Demba S, Yokozaki H, Tahara E. Reduced expression of cyclin-dependent kinase inhibitor p27Kip 1 is associated with advanced stage and invasiveness of gastric carcinomas. Jpn J Cancer Res 1997;88:625–629.
Sakaguchi T, Watanabe A, Sawada H, Yamada Y, Yamashita J, Matsuda M, et al. Prognostic value of cyclin E and p53 expression in gastric carcinoma. Cancer 1998;82:1238–1243.
Fukuse T, Hirata T, Naiki H, Hitomi S, Wada H. Prognostic significance of cyclin E overexpression in resected non-small cell lung cancer. Cancer Res 2000;60:242–244.
Mishina T, Dosaka-Akita H, Hommura F, Nishi M, Kojima T, Ogura S, et al. Cyclin E expression, a potential prognostic marker for non-small cell lung cancers. Clin Cancer Res 2000;6:11–16.
Furihata M, Ohtsuki Y, Sonobe H, Shuin T, Yamamoto A, Terao N, Kuwahara M. Prognostic significance of cyclin E and p53 protein overexpression in carcinoma of the renal pelvis and ureter. Br J Cancer 1998;77:783–788.
Erlanson M, Portin C, Linderholm B, Lindh J, Roos G, Landberg G. Expression of cyclin E and the cyclin-dependent kinase inhibitor p27 in malignant lymphomas-prognostic implications. Blood 1998;92:770–777.
Yokozawa T, Towatari M, Iida H, Takeyama K, Tanimoto M, Kiyoi H, et al. Prognostic significance of the cell cycle inhibitor p27K’P1 in acute myeloid leukemia. Leukemia 2000;14:28–33.
Dellas A, Schultheiss E, Leivas MR, Moch H, Torhorst J. Association of p27K’Pl cyclin E and c-myc expression with progression and prognosis in HPV-positive cervical neoplasms. Anticancer Res 1998;18:3991–3998.
Eguchi N, Fujii K, Tsuchida A, Yamamoto S, Sasaki T, Kajiyama G. Cyclin E overexpression in human gallbladder carcinomas. Oncol Rep 1999;6:93–96.
Lu X, Toki T, Konishi I, Nikaido T, Fujii S. Expression of p21wAFVCrn1 in adenocarcinoma of the uterine cervix: a possible immunohistochemical marker of a favorable prognosis. Cancer 1998;82:2409–2417.
Shimizu M, Nikaido T, Toki T, Shiozawa T, Fujii S. Clear cell carcinoma has an expression pattern of cell cycle regulatory molecules that is unique among ovarian adenocarcinomas. Cancer 1999;85:669–677.
Chang WY, Birch L, Woodham C, Gold LI, Prins GS. Neonatal estrogen exposure alters the transforming growth factor-beta signaling system in the developing rat prostate and blocks the transient p21(cipl/wafl) expression associated with epithelial differentiation. Endocrinology 1999;140:2801–2813.
Natsugoe S, Nakashima S, Matsumoto M, Xiangming C, Okumura H, Kijima F, et al. Expression of p21 WAFT/Cipl in the p53-dependent pathway is related to prognosis in patients with advanced esophageal carcinoma. Clin Cancer Res 1999;5:2445–2449.
Nita ME, Nagawa H, Tominaga O, Tsuno N, Hatano K, Kitayama J, et al. p21wafuc’Pl expression is a prognostic marker in curatively resected esophageal squamous cell carcinoma, but not p27K`P1, p53, or Rb. Ann Surg Oncol 1999;6:481–488.
Lam KY, Law S, Tin L, Tung PH, Wong J. The clinicopathological significance of p21 and p53 expression in esophageal squamous cell carcinoma: an analysis of 153 patients. Am J Gastroenterol 1999;94:2060–2068.
Osaki T, Kimura T, Tatemoto Y, Dapeng L, Yoneda K, Yamamoto T. Diffuse mode of tumor cell invasion and expression of mutant p53 protein but not of p21 protein are correlated with treatment failure in oral carcinomas and their metastatic foci. Oncology 2000;59:36–43.
Hirvikoski P, Kellokoski JK, Kumpulainen EJ, Virtaniemi JA, Johansson RT, Kosma VM. Downregulation of p21/WAF1 is related to advanced and dedifferentiated laryngeal squamous cell carcinoma. J Clin Pathol 1999;52:440–444.
Qiu H, Sirivongs P, Rothenberger M, Rothenberger DA, Garcia-Aguilar J. Molecular prognostic factors in rectal cancer treated by radiation and surgery. Dis Colon Rectum 2000;43:451–459.
Zirbes TK, Baldus SE, Moenig SP, Nolden S, Kunze D, Shafizadeh ST, et al. Prognostic impact of p21/wafl/cipl in colorectal cancer. Int J Cancer 2000;89:14–18.
Ropponen KM, Kellokoski JK, Lipponen PK, Pietilainen T, Eskelinen MJ, Alhava EM, Kosma VM. p21/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis. Br J Cancer 1999;81:133–140.
Barbareschi M, Pelosio P, Caffo O, Buttita F, Pellegrini S, Barbazza R, et al. Cyclin-Dl gene amplification and expression in breast carcinoma: relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21WAF1 immunohistochemical expression. Int J Cancer (Pred Oncol) 1997;74;171–174.
Mathoulin-Portier MP, Viens P, Cowen D, Bertucci F, Houvenaeghel G, Geneix J, et al. Prognostic value of simultaneous expression of p21 and mdm2 in breast carcinomas treated by adjuvant chemotherapy with antracyclin. Oncol Rep 2000;7:675–680.
Anttila MA, Kosma VM, Hongxiu J, Puolakka J, Juhola M, Saarikoski S, Syrjanen K. p21/ WAF1 expression as related to p53, cell proliferation and prognosis in epithelial ovarian cancer. Br J Cancer 1999;79:1870–1878.
Costa MI, Hansen CL, Walls JE, Scudder SA Immunohistochemical markers of cell cycle control applied to ovarian and primary peritoneal surface epithelial neoplasms: p21(WAF1/ CIP1) predicts survival and good response to platinin-based chemotherapy. Hum Pathol 1999;30:640–647.
Schmider A, Gee C, Friedmann W, Lukas JJ, Press MF, Lichtenegger W, Reles A. p21 (WAF1/CIP1) protein expression is associated with prolonged survival but not with p53 expression in epithelial ovarian carcinoma. Gynecol Oncol 2000;77:237–242.
Werness BA, Freedman AN, Piver MS, Romero-Gutierrez M, Petrow E. Prognostic significance of p53 and p21(waf 1 /cip 1) immunoreactivity in epithelial cancers of the ovary. Gynecol Oncol 1999;75:413–418.
Baekelandt M, Holm R, Trope CG, Nesland JM, Kristensen GB. Lack of independent prognostic significance of p21 and p27 expression in advanced ovarian cancer: an immunohistochemical study. Clin Cancer Res 1999;5:2848–2853.
Kaye PV, Radebold K, Isaacs S, Dent DM. Expression of p53 and p21waf1/cipl in gastric carcinoma: lack of inter-relationship or correlation with prognosis. Eur J Surg Oncol 2000;26:39–43.
Ikeguchi M, Saito H, Kondo A, Tsujitani S, Maeta M, Kaibara N. Mutated p53 protein expression and proliferative activity in advanced gastric cancer. Hepatogastroenterology 1999;46:2648–2653.
Baretton GB, Klenk U, Diebold J, Schmeller N, Lohrs U. Proliferation-and apoptosis-associated factors in advanced prostatic carcinomas before and after androgen deprivation therapy: prognostic significance of p21/WAF1/CIP1 expression. Br J Cancer 1999;80:546–555.
Nio Y, Dong M, Uegaki K, Hirahara N, Minari Y, Sasaki S, et al. Comparative significance of p53 and WAF/1-p21 expression on the efficacy of adjuvant chemotherapy for resectable invasive ductal carcinoma of the pancreas. Pancreas 1999;18:117–126.
Vonlanthen S, Heighway J, Kappeler A, Altermatt HJ, Borner MM, Betticher DC. p21 is associated with cyclin D1, p16INK4a and pRb expression in resectable non-small cell lung cancer. Int J Oncol 2000;16:951–957.
Aikawa H, Sato M, Fujimura S, Takahashi H, Endo C, Sakurada A, et al. MDM2 expression is associated with progress of disease and WAF1 expression in resected lung cancer. Int J Mol Med 2000;5:631–633.
Karjalainen JM, Eskelinen MJ, Kellokoski JK, Reinikainen M, Alhava EM, Kosma VM. p21(WAF 1/CIP 1) expression in stage I cutaneous malignant melanoma: its relationship with p53, cell proliferation and survival. Br J Cancer 1999;79:895–902.
Smolewski P, Niewiadomska H, Krykowski E, Robak T. Expression of p21 and MDM-2 proteins on tumor cells in responding and non-responding patients with Hodgkin’s disease. Neoplasma 1999;46:212–218.
Zhang A, Ohshima K, Sato K, Kanda M, Suzumiya J, Shimazaki K, et al. Prognostic clinicopathologic factors, including immunologic expression in diffuse large B-cell lymphomas. Pathol Int 1999;49:1043–1052.
Chow NH, Tzai TS, Cheng HL, Liu HS, Chan SH, Tong YC. The clinical value of p2lw’Fv CIPI expression in superficial bladder cancer. Anticancer Res 2000;20:1173–1176.
Korkolopoulou P, Christodoulou P, Konstantinidou AE, Thomas-Tsagli E, Kapralos P, Davaris P. Cell cycle regulators in bladder cancer: a multivariate survival study with emphasis on p27K’Pl. Hum Pathol 2000;31:751–760.
Kirla R, Salminen E, Huhtala S, Nuutinen J, Talve L, Haapasalo H, Kalim H. Prognostic value of the expression of tumor suppressor genes p53, p21, p16 and prb, and Ki-67 labelling in high grade astrocytomas treated with radiotherapy. J Neurooncol 2000;46:71–80.
Han EK, Begemann M, Sgambato A, Soh JW, Doki Y, Xing WQ, Liu W, Weinstein IB. Increased expression of cyclin D1 in a murine mammary epithelial cell line induces p27k’P1, inhibits growth and enhances apoptosis. Cell Growth Differ 1996;7:699–710.
Catzavelos C, Tsao MS, DeBoer G, Bhattacharya N, Shepherd FA, Slingerland JM. Reduced expression of the cell cycle inhibitor p27Kip 1 in non-small cell lung carcinoma: a prognostic factor independent of Ras. Cancer Res 1999;59:684–688.
Gillett CE, Smith P, Peters G, Lu X, Barnes DM. Cyclin-dependent kinase inhibitor p27Kip 1 expression and interaction with other cell cycle-associated proteins in mammary carcinoma. J Pathol 1999;187:200–206.
Tsuchiya A, Zhang GJ, Kanno M. Prognostic impact of cyclin-dependent kinase inhibitor p27k’Pl in node-positive breast cancer. J Surg Oncol 1999;70:230–234.
Wu SG, el-Deiry WS. p53 and chemosensitivity. Nat Med 1996;2:255–256.
Barbareschi M, van Tinteren H, Mauri FA, Veronese S, Peterse H, Maisonneuve P, et al. p27(kip 1) expression in breast carcinomas: an immunohistochemical study on 512 patients with long-term follow-up. Int J Cancer 2000;89:236–241.
Loda M, Cukor B, Tam SW, Lavin P, Firentino M, Draetta GF, Jessup JM, Pagano M. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 1997;3:231–234.
Palmgvist R, Stenling R, Oberg A, Landberg G. Prognostic significance of p27(Kip 1) expression in colorectal cancer: a clinico-pathological characterization. J Pathol 1999;188:18–23.
Thomas GV, Szigeti K, Murphy M, Draetta G, Pagano M, Loda M. Down-regulation of p27 is associated with development of colorectal adenocarcinoma metastases. Am J Pathol 1998;153:681–687.
Tenjo T, Toyoda M, Okuda J, Watanabe I, Yamamoto T, Tanaka K, et al. Prognostic significance of p27(kipl) protein expression and spontaneous apoptosis in patients with colorectal adenocarcinomas. Oncology 2000;58:45–51.
Yao J, Eu KW, Seow-Choen F, Cheah PY. Down-regulation of p27 is a significant predictor of poor overall survival and may facilitate metastasis in colorectal carcinomas. Int J Cancer 2000;89:213–216.
Mori M, Mimori K, Shiraishi T, Tanaka S, Ueo H, Sugimachi K, Akiyoshi T. p27 expression and gastric carcinoma. Nature Med 1997;3:593.
Ohtani M, Isozaki H, Fujii K, Nomura E, Niki M, Mabuchi H, et al. Impact of the expression of cyclin-dependent kinase inhibitor p27Kip 1 and apoptosis in tumor cells on the overall survival of patients with non-early stage gastric carcinoma. Cancer 1999;85:1711–1718.
Kwon OJ, Kang HS, Suh JS, Chang MS, Jang JJ, Chung JK. The loss of p27 protein has an independent prognostic significance in gastric cancer. Anticancer Res 1999;19:4215–4220.
Cote RJ, Shi YF, Groshen S, Feng A-C, Cordon-Cardo C, Skinner DG, Lieskovsky G. Association of p27Kipl levels with recurrence and survival in patients with stage C prostate carcinoma. J Nat Canc Inst 1998;90:916–920.
De Marzo AM, Meeker AK, Epstein JI, Coffy DS. Prostate stem cell compartments: expression of the cell cycle inhibitor p271(’PI in normal, hyperplastic, and neoplastic cells. Am J Pathol 1998;153:911–919.
Tsihlias J, Kapsta LR, DeBoer G, Morava-Protzer I, Zbieranowski I, Bhattacharya N, et al. Loss of cyclin-dependent kinase inhibitor p27K’PI is a novel prognostic factor in localized human prostate adenocarcinoma. Cancer Res 1998;58:542–548.
Yang RM, Naitoh J, Murphy M, Wang HJ, Phillipson J, deKernion JB, et al. Low p27 expression predicts poor disease-free survival in patients with prostate cancer. J Urol 1998;159:941–945.
Erdamar S, Yang G, Harper JW, Lu X, Kattan MW, Thompson TC, Wheeler TM. Levels of expression of p27KIP1 protein in human prostate and prostate cancer: an immunohistochemical analysis. Mod Pathol 1999;12:751–755.
Masciullo V, Sgambato A, Pacilio C, Pucci B, Ferrandina G, Palazzo J, et al. Frequent loss of expression of the cyclin-dependent kinase inhibitor p27 in epithelial ovarian cancer. Cancer Res 1999;59:3790–3794.
Singh SP, Lipman J, Goldman H, Ellis FH Jr, Aizenman L, Cangi MG, et al. Loss or altered subcellular localization of p27 in Barrett’s associated adenocarcinoma. Cancer Res 1998;58:1730–1735.
Hui AM, Li X, Shi YZ, Torzilli G, Takayama T, Makuuchi M. p27(Kipl) expression in normal epithelia, precancerous lesions, and carcinomas of the gallbladder: association with cancer progression and prognosis. Hepatology 2000;31:1068–1072.
Shamma A, Doki Y, Tsujinaka T, Shiozaki H, Inoue M, Yano M, et al. Loss of p27(KIP1) expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Oncology 2000;58:152–158.
Fan GK, Fujieda S, Sunaga H, Tsuzuki H, Ito N, Saito H. Expression of protein p27 is associated with progression and prognosis in laryngeal cancer. Laryngoscope 1999; 109:815–820.
Venkatesan TK, Kuropkat C, Caldarelli DD, Panje WR, Hutchinson JC Jr, Chen S, Coon JS. Prognostic significance of p27 expression in carcinoma of the oral cavity and oropharynx. Laryngoscope 1999;109:1329–1333.
Oka K, Suzuki Y, Nakano T. Expression of p27 and p53 in cervical squamous cell carcinoma patients treated with radiotherapy alone. Cancer 2000;88:2766–2773.
Esposito V, Baldi A, De Luca A, Groger AM, Loda M, Giordano GG, et al. Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res 1997;57:3381–3385.
Ishihara S, Minato K, Hoshino H, Saito R, Hara F, Nakajima T, Mori M. The cyclin-dependent kinase inhibitor p27 as a prognostic factor in advanced non-small cell lung cancer: its immunohistochemical evaluation using biopsy specimens. Lung Cancer 1999;26:187–194.
Taga S, Osaki T, Ohgami A, Imoto H, Yoshimatsu T, Yoshino I, et al. Prognostic value of the immunohistochemical detection of p161NK4 expression in nonsmall cell lung carcinoma. Cancer 1997;80:389–395.
Okamoto A, Hussain SP, Hagiwara K, Spillare EA, Rusin MR, Demetrick DJ, et al. Mutations in the p 161NK4/MTS I/CDKN2 p 151NK4B /MT S2 and p18 genes in primary and metastatic lung cancer. Cancer Res 1995;55:1448–1451.
Yatabe Y, Masuda A, Koshikawa T, Nakamura S, Kuroishi T, Osada H, et al. p27K1P1 in human lung cancers: differential changes in small cell and non-small cell carcinomas. Cancer Res 1998;58:1042–1047.
Gazzeri S, Gouyer V. Inactivation of RB gene and pRB function in lung cancer, in Lung Tumors: Fundamental Biology and Clinical Management, Brambilla C, Brambilla E, eds. Marcel Dekker, New York, 1998.
Sanchez-Beato M, Saez AI, Martinez JC, Mateo MS, Sanchez LS, Villuendas R, et al. Cyclindependent kinase inhibitor p271uP1 in lymphoid tissue: p2711p1 expression is inversely proportional to the proliferative index. Am J Pathol 1997;151:151–160.
Fuse T, Tanikawa M, Nakanishi M, Ikeda K, Tada T, Inagaki H, et al. p2716P1 expression by contact inhibition as a prognostic index of human glioma. J Neurochem 2000;74:1393–1399.
Cavalla P, Piva R, Bortolotto S, Grosso R, Cancelli I, Chio A, Schiffer D. p27/kipl expression in oligodendrogliomas and its possible prognostic role. Acta Neuropathol (Berl) 1999; 98:629–634.
Taniguchi T, Chikatsu N, Takahashi S, Fujita A, Uchimaru K, Asano S, et al. Expression of p 16INK4A and p14ARF in hematological malignancies. Leukemia 1999;13:1760–1769.
Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, et al. Germline p16 mutations in familial melanoma. Nat Genet 1994;8:15–21.
Straume O, Sviland L, Akslen LA. Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma. Clin Cancer Res 2000;6:1845–1853.
Chana JS, Grover R, Wilson GD, Hudson DA, Forders M, Sanders R, Grobbelaar AO. An analysis of p16 tumour suppressor gene expression in acral lentiginous melanoma. Br J Plast Surg 2000;53:46–50.
Straume O, Akslen LA. Alterations and prognostic significance of p16 and p53 protein expression in subgroups of cutaneous melanoma. Int J Cancer 1997;74:535–539.
Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16 (INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 2001;92:276–284.
Salvesen HB, Das S, Akslen LA. Loss of nuclear p16 protein expression is not associated with promoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis. Clin Cancer Res 2000;6:153–159.
Dong Y, Walsh MD, McGuckin MA, Cummings MC, Gabrielli BG, Wright GR, et al. Reduced expression of retinoblastoma gene product (pRB) and high expression of p53 are associated with poor prognosis in ovarian cancer. Int J Cancer 1997;74:407–415.
Barbieri F, Cagnoli M, Ragni N, Pedulla F, Foglia G, Alama A. Expression of cyclin D1 correlates with malignancy in human ovarian tumours. Br J Cancer 1997;75:1263–1268.
Hu YX, Watanabe H, Ohtsubo K, Yamaguchi Y, Ha A, Okai T, Sawabu N. Frequent loss of p16 expression and its correlation with clinicopathological parameters in pancreatic carcinoma. Clin Cancer Res 1997;3:1473–1477.
Volm M, Koomagi R, Mattem J. Prognostic value of p l6INK4A expression in lung adenocarcinoma. Anticancer Res 1998;18:2309–2312.
Xu L, Sgroi D, Sterner CJ, Beauchamp RL, Pinney DM, Keel S, et al. Mutational analysis of CDKN2 (MTS1/p16ink4) in human breast carcinomas. Cancer Res 1994;54:5262–5264.
Dublin EA, Patel NK, Gillett CE, Smith P, Peters G, Barnes DM. Retinoblastoma and p16 proteins in mammary carcinoma: their relationship to cyclin D1 and histopathological parameters. Int J Cancer 1998;79:71–75.
Tsujie M, Yamamoto H, Tomita N, Sugita Y, Ohue M, Sakita I, et al. Expression of tumor suppressor gene p16(INK4) products in primary gastric cancer. Oncology 2000;58:126–136.
Huang CI, Taki T, Higashiyama M, Kohno N, Miyake M. p16 protein expression is associated with a poor prognosis in squamous cell carcinoma of the lung. Br J Cancer 2000; 82:374–380.
Kawabuchi B, Moriyama S, Hironaka M, Fujii T, Koike M, Moriyama H, et al. p16 inactivation in small-sized lung adenocarcinoma: its association with poor prognosis. Int J Cancer 1999;84:49–53.
Kratzke RA, Greatens TM, Rubins JB, Maddaus MA, Niewoehner DE, Niehans GA, Geradts J. Rb and p16INK4a expression in resected non-small cell lung tumors. Cancer Res 1996;56:3415–3420.
Groeger AM, Caputi M, Esposito V, De Luca A, Bagella L, Pacilio C, et al. Independent prognostic role of p16 expression in lung cancer. J Thorac Cardiovasc Surg 1999;118:529–535.
Hommura F, Dosaka-Akita H, Kinoshita I, Mishina T, Hiroumi H, Ogura S, et al. Predictive value of expression of pl6INK4A, retinoblastoma and p53 proteins for the prognosis of nonsmall-cell lung cancers. Br J Cancer 1999;81:696–701.
Gorgoulis VG, Zacharatos P, Kotsinas A, Liloglou T, Kyroudi A, Veslemes M, et al. Alterations of the p16-pRb pathway and the chromosome locus 9p21–22 in non-small-cell lung carcinomas: relationship with p53 and MDM2 protein expression. Am J Pathol 1998; 153:1749–1765.
Mekki Y, Catallo R, Bertrand Y, Manel AM, Ffrench P, Baghdassarian N, et al. Enhanced expression of p 16ink4a is associated with a poor prognosis in childhood acute lymphoblastic leukemia. Leukemia 1999;13:181–189.
Kees UR, Burton PR, Lu C, Baker DL. Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome. Blood 1997;89:4161–4166.
Diccianni MB, Batova A, Yu J, Vu T, Pullen J, Amylon M, Pollock BH, Yu AL. Shortened survival after relapse in T-cell acute lymphoblastic leukemia patients with p16/p15 deletions. Leuk Res 1997;21:549–558.
Yamada Y, Hatta Y, Murata K, Sugawara K, Ikeda S, Mine M, et al. Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia. J Clin Oncol 1997;15: 1778–1785.
Garcia-Sanz R, Gonzalez M, Vargas M, Chillon MC, Balanzategui A, Barbon M, et al. Deletions and rearrangements of cyclin-dependent kinase 4 inhibitor gene p16 are associated with poor prognosis in B cell non-Hodgkin’s lymphomas. Leukemia 1997; 11:1915–1920.
Gronbaek K, de Nully Brown P, Moller MB, Nedergaard T, Ralfkiaer E, Moller P, et al. Concurrent disruption of pl61NK4a and the ARF-p53 pathway predicts poor prognosis in aggressive non-Hodgkin’s lymphoma. Leukemia 2000 Oct;14(10):1727–1735.
Guenova M, Rassidakis GZ, Gorgoulis VG, Angelopoulou MK, Siakantaris MR, Kanavaros P, et al. pl61NK4A is regularly expressed in Hodgkin’s disease: comparison with retinoblastoma, p53 and MDM2 protein status, and the presence of Epstein-Barr virus. Mod Pathol 1999;12:1062–1071.
Takita J, Hayashi Y, Nakajima T, Adachi J, Tanaka T, Yamaguchi N, et al. The p16 (CDKN2A) gene is involved in the growth of neuroblastoma cells and its expression is associated with prognosis of neuroblastoma patients. Oncogene 1998;17:3137–3143.
Bortolotto S, Chiado-Piat L, Cavalla P, Bosone I, Chio A, Mauro A, Schiffer D. CDKN2A/ p16 inactivation in the prognosis of oligodendrogliomas. Int J Cancer 2000;88:554–557.
Puduvalli VK, Kyritsis AP, Hess KR, Bondy ML, Fuller GN, Kouraklis GP, et al. Patterns of expression of Rb and p16 in astrocytic gliomas, and correlation with survival. Int J Oncol 2000;17:963–969.
Orlow I, Drobnjak M, Zhang ZF, Lewis J, Woodruff JM, Brennan MF, Cordon-Cardo C. Alterations of INK4A and INK4B genes in adult soft tissue sarcomas: effect on survival. J Natl Cancer Inst 1999;91:73–79.
Miettinen H, Kononen J, Sallinen P, Alho H, Helen P, Helin H, et al. CDKN2/p16 predicts survival in oligodendrogliomas: comparison with astrocytomas. J Neurooncol 1999; 41:205–211.
Orlow I, LaRue H, Osman I, Lacombe L, Moore L, Rabbani F, et al. Deletions of the INK4A gene in superficial bladder tumors. Association with recurrence. Am J Pathol 1999;155: 105–113.
Faded S, Kantarjian HM, Manshouri T, Chan CY, Pierce S, Hays KJ, et al. The prognostic significance of pl6INK4a/p14ARF and pl5INK4b deletions in adult acute lymphoblastic leukemia. Clin Cancer Res 1999;5:1855–1861.
Wong IH, Ng MH, Huang DP, Lee JC. Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Blood 2000;95:1942–1949.
Zhou M, Gu L, Yeager AM, Findley HW. Incidence and clinical significance of CDKN2/ MTS 1 /P16Ink4A and MTS2/P15Ink4B gene deletions in childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 1997;14:141–150.
Quesnel B, Guillerm G, Vereecque R, Wattel E, Preudhomme C, Bauters F, et al. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 1998;91:2985–2990.
Berns EM, de Klein A, van Putten WL, van Staveren IL, Bootsma A, Klijn JG, Foekens JA. Association between RB-1 gene alterations and factors of favourable prognosis in human breast cancer, without effect on survival. Int J Cancer 1995;64:140–145.
Pietilainen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma VM, Syrjanen K. Expression of retinoblastoma gene protein (Rb) in breast cancer as related to established prognostic factors and survival. Eur J Cancer 1995;31A:329–333.
Sawan A, Randall B, Angus B, Wright C, Henry JA, Ostrowski J, et al. Retinoblastoma and p53 gene expression related to relapse and survival in human breast cancer: an immunohistochemical study. J Pathol 1992;168(1):23–28.
Poller DN, Baxter KJ, Shepherd NA. p53 and Rbl protein expression: are they prognostically useful in colorectal cancer? Br J Cancer 1997;75:87–93.
Naka T, Toyota N, Kaneko T, Kaibara N. Protein expression of p53, p21WAF1, and Rb as prognostic indicators in patients with surgically treated hepatocellular carcinoma. Anticancer Res 1998;18:555–564.
Vargas MP, Vargas HI, Kleiner DE, Merino MJ. Adrenocortical neoplasms: role of prognostic markers MIB-1, P53, and RB. Am J Surg Pathol 1997;21:556–562.
Dokiya F, Ueno K, Ma S, Eizuru Y, Furuta S, Ohyama M. Retinoblastoma protein expression and prognosis in laryngeal cancer. Acta Otolaryngol 1998;118:759–762.
Girod SC, Pfeiffer P, Ries J, Pape HD. Proliferative activity and loss of function of tumour suppressor genes as `biomarkers’ in diagnosis and prognosis of benign and preneoplastic oral lesions and oral squamous cell carcinoma. Br J Oral Maxillofac Surg 1998;36:252–260.
Guerry M, Vabre L, Talbot M, Mamelle G, Leridant AM, Hill C, et al. Prognostic value of histological and biological markers in pharyngeal squamous cell carcinoma: a case-control study. Br J Cancer 1998;77:1932–1936.
Hashimoto N, Tachibana M, Dhar DK, Yoshimura H, Nagasue N. Expression of p53 and RB proteins in squamous cell carcinoma of the esophagus: their relationship with clinicopathologic characteristics. Ann Surg Oncol 1999;6:489–494.
Ikeguchi M, Oka S, Gomyo Y, Tsujitani S, Maeta M, Kaibara N. Clinical significance of retinoblastoma protein (pRB) expression in esophageal squamous cell carcinoma. J Surg Oncol 2000;73:104–108.
Zur Hausen A, Sarbia M, Heep H, Willers R, Gabbert HE. Retinoblastoma-protein (prb) expression and prognosis in squamous-cell carcinomas of the esophagus. Int J Cancer 1999;22;84:618–622.
Cordon-Cardo C, Wartinger D, Petrylak D, Dalbagni G, Fair WR, Fuks Z, Reuter VE. Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer. J Natl Cancer Inst 1992;84:1251–1256.
Cote RJ, Dunn MD, Chatterjee SJ, Stein JP, Shi SR, Tran QC, et al. Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res 1998;58:1090–1094.
Grossman HB, Liebert M, Antelo M, Dinney CP, Hu SX, Palmer JL, Benedict WF. p53 and RB expression predict progression in T1 bladder cancer. Clin Cancer Res 1998;4:829–834.
Jahnson S, Risberg B, Karlsson MG, Westman G, Bergstrom R, Pedersen J. p53 and Rb immunostaining in locally advanced bladder cancer: relation to prognostic variables and predictive value for the local response to radical radiotherapy. Eur Urol 1995;28:135–142.
Lipponen PK, Liukkonen TJ. Reduced expression of retinoblastoma (Rb) gene protein is related to cell proliferation and prognosis in transitional-cell bladder cancer. J Cancer Res Clin Oncol 1995;121:44–50.
Logothetis CJ, Xu HJ, Ro JY, Hu SX, Sahin A, Ordonez N, Benedict WF. Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. J Natl Cancer Inst 1992;84:1256–1261.
Pollack A, Czerniak B, Zagars GK, Hu SX, Wu CS, Dinney CP, et al. Retinoblastoma protein expression and radiation response in muscle-invasive bladder cancer. Int J Radiat Oncol Biol Phys 1997;39:687–695.
Tetu B, Fradet Y, Allard P, Veilleux C, Roberge N, Bernard P. Prevalence and clinical significance of HER/2neu, p53 and Rb expression in primary superficial bladder cancer. J Urol 1996;155:1784–1788.
Xu HJ, Quinlan DC, Davidson AG, Hu SX, Summers CL, Li J, Benedict WF. Altered retinoblastoma protein expression and prognosis in early-stage non-small-cell lung carcinoma. J Natl Cancer Inst 1994;86:695–699.
Xu HJ, Cagle PT, Hu SX, Li J, Benedict WF. Altered retinoblastoma and p53 protein status in non-small cell carcinoma of the lung: potential synergistic effects on prognosis. Clin Cancer Res 1996;2:1169–1176.
Volm M, Stammler G. Retinoblastoma (Rb) protein expression and resistance in squamous cell lung carcinomas. Anticancer Res 1996;16:891–894.
Wurl P, Meye A, Berger D, Lautenschlager C, Bache M, Holzhausen HJ, et al. Significance of retinoblastoma and mdm2 gene expression as prognostic markers for soft-tissue sarcoma. Langenbecks Arch Surg 1998;383:99–103.
Cance WG, Brennan MF, Dudas ME, Huang CM, Cordon-Cardo C. Altered expression of the retinoblastoma gene product in human sarcomas. N Engl J Med 1990;323:1457–1462.
Benassi MS, Molendini L, Gamberi G, Sollazzo MR, Ragazzini P, Merli M, et al. Altered G1 phase regulation in osteosarcoma. Int J Cancer 1997;74:518–522.
Kornblau SM, Xu HJ, Zhang W, Hu SX, Beran M, Smith TL, et al. Levels of retinoblastoma protein expression in newly diagnosed acute myelogenous leukemia. Blood 1994; 84:256–261.
Kornblau SM, Andreeff M, Hu SX, Xu HJ, Patel S, Theriault A, et al. Low and maximally phosphorylated levels of the retinoblastoma protein confer poor prognosis in newly diagnosed acute myelogenous leukemia: a prospective study. Clin Cancer Res 1998; 4:1955–1963.
Morente MM, Piris MA, Abraira V, Acevedo A, Aguilera B, Bellas C, Fraga M, et al. Adverse clinical outcome in Hodgkin’s disease is associated with loss of retinoblastoma protein expression, high Ki67 proliferation index, and absence of Epstein-Barr virus-latent membrane protein 1 expression. Blood 1997;90:2429–2436.
Sanchez E, Chacon I, Plaza MM, Munoz E, Cruz MA, Martinez B, et al. Clinical outcome in diffuse large B-cell lymphoma is dependent on the relationship between different cell-cycle regulator proteins. J Clin Oncol 1998;16:1931–1939.
Sauerbrey A, Stammler G, Zintl F, Volm M. Expression and prognostic value of the retino-blastoma tumour suppressor gene (RB-1) in childhood acute lymphoblastic leukaemia. Br J Haematol 1996;94:99–104.
Tsai T, Davalath S, Rankin C, Radich JP, Head D, Appelbaum FR, Boldt DH. Tumor suppressor gene alteration in adult acute lymphoblastic leukemia (ALL). Analysis of retinoblastoma (Rb) and p53 gene expression in lymphoblasts of patients with de novo, relapsed, or refractory ALL treated in Southwest Oncology Group studies. Leukemia 1996;10:1901–1910.
Massaro-Giordano M, Baldi G, De Luca A, Baldi A, Giordano A. Differential expression of the retinoblastoma gene family members in choroidal melanoma: prognostic significance. Clin Cancer Res 1999;5:1455–1458.
Leoncini L, Bellan C, Cossu A, Claudio PP, Lazzi S, Cinti C, et al. Retinoblastoma-related p107 and pRb2/p 130 proteins in malignant lymphomas: distinct mechanisms of cell growth control. Clin Cancer Res 1999 Dec;5(12):4065–4072.
Susini T, Baldi F, Howard CM, Baldi A, Taddei G, Massi D, et al. Expression of the retinoblastoma-related gene Rb2/p130 correlates with clinical outcome in endometrial cancer. J Clin Oncol 1998;16:1085–1093.
Zheng W, Cao P, Zheng M, Kramer EE, Godwin TA. p53 overexpression and bcl-2 persistence in endometrial carcinoma: comparison of papillary serous and endometrioid subtypes. Gynecol Oncol 1996;61:167–174.
Ramael M, Lemmens G, Eerdekens C, Buysse C, Deblier I, Jacobs W, van Marck E. Immunoreactivity for p53 protein in malignant mesothelioma and non-neoplastic mesothelium. J Pathol. 1992;168:371–375.
Polkowski W, Baak JP, van Lanschot JJ, Meijer GA, Schuurmans LT, Ten Kate FJ, et al. Clinical decision making in Barrett’s oesophagus can be supported by computerized immunoquantitation and morphometry of features associated with proliferation and differentiation. J Pathol 1998;184:161–168.
Van Sandick JW, Baak JP, van Lanschot JJ, Polkowski W, ten Kate FJ, Obertop H, Offerhaus GJ. Computerized quantitative pathology for the grading of dysplasia in surveillance biopsies of Barrett’s oesophagus. J Pathol 2000;190:177–183.
Thor AD, Moore DH II, Edgerton SM, Kawasaki ES, Reihsaus E, Lynch HT, et al. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst 1992;84:845–855.
Andersen TI, Holm R, Nesland JM, Heimdal KR, Ottestad L, Borresen AL. Prognostic significance of TP53 alterations in breast carcinoma. Br J Cancer 1993;68:540–548.
Maeda K, Chung Y, Kang S, Ogawa M, Onoda N, Nishiguchi Y, et al. Cyclin D1 overexpression and prognosis in colorectal adenocarcinoma. Oncology 1998;55:145–151.
Kobayashi S, Koide Y, Endo M, Isono K, Ochiai T. The p53 gene mutation is of prognostic value in esophageal squamous cell carcinoma patients in unified stages of curability. Am J Surg 1999;177:497–502.
Louie DC, Offit K, Jaslow R, Parsa NZ, Murty VV, Schluger A, Chaganti RS. p53 overexpression as a marker of poor prognosis in mantle cell lymphomas with t(11;14) (g13;g32). Blood 1995;86:2892–2899.
Xiong Y, Zhang H, Beach D. Subunit rearrangement of the cyclin-dependent kinase is associated with cellular transformation. Genes Dey 1993;7:1572–1583.
Sui L, Dong Y, Ohno M, Goto M, Inohara T, Sugimoto K, et al. Inverse Expression of Cdk4 and p16 in Epithelial Ovarian Tumors. Gynecol Oncol 2000;79:230–237.
Aas T, Borresen AL, Geisler S, Smith-Sorensen B, Johnsen H, Varhaug JE, et al. Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 1996;2:811–814.
Righetti SC, Della Torre G, Pilotti S, Menard S, Ottone F, Colnaghi MI, et al. A comparative study of p53 gene mutations, protein accumulation, and response to cisplatin-based chemotherapy in advanced ovarian carcinoma. Cancer Res 1996;56:689–693.
Rusch V, Klimstra D, Venkatraman E, Oliver J, Martini N, Gralla R, et al. Aberrant p53 expression predicts clinical resistance to cisplatin-based chemotherapy in locally advanced non-small cell lung cancer. Cancer Res 1995;55:5038–5042.
Blagosklonny MV, el-Deiry WS. Acute overexpression of wt p53 facilitates anticancer drug-induced death of cancer and normal cells. Int J Cancer 1998;75:933–940.
Bergers E, Jannink I, Van Diest PJ, Baak JPA. Influence of fixation delay on mitotic activity and flow cytometric %S-phase. Hum Pathol 1997;28:95–100.
Van Diest Pi, Baak JPA, Matze-Cok P, Wisse-Brekelmans ECM, Galen CM van, Kurver PHJ, et al. Reproducibility of mitosis counting in 2469 breast cancer specimens: results from the Multicenter Morphometric Mammary Carcinoma Project. Hum Pathol 1992; 23:603–607.
Jannink I, Van Diest PJ, Baak JPA. Comparison of the prognostic value of Mitotic Activity Index (MAI), random MAI (rMAI), MN-index, and random MN-index (rMN-index) in breast cancer patients. Hum Pathol 1995;26:1086–1092.
Jannink I, Van Diest Pi, Baak JPA. Comparison of the prognostic value of mitotic frequency and mitotic activity index in breast cancer. Breast 1996;5:31–36.
Jannink I, Risberg B, Van Diest Pi, Baak JPA. Heterogeneity of mitoses counting in breast cancer. Histopathology 1996;29:421–428.
Michaelides R, van Tinteren H, Balkenende A, et al. Cyclin A is a prognostic indicator in early stage breast cancer with and without tamoxifen treatment. Br J Cancer 2002;86: 402–408.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer Science+Business Media New York
About this chapter
Cite this chapter
van Diest, P.J., Michalides, R.J.A.M. (2003). Cell Cycle Regulators. In: Giordano, A., Soprano, K.J. (eds) Cell Cycle Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-401-6_9
Download citation
DOI: https://doi.org/10.1007/978-1-59259-401-6_9
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-61737-257-5
Online ISBN: 978-1-59259-401-6
eBook Packages: Springer Book Archive