Skip to main content

Advertisement

SpringerLink
Log in

Increased SIAH expression predicts ductal carcinoma in situ (DCIS) progression to invasive carcinoma

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Hyperactivated HER2/Neu/EGFR/RAS signaling is a major growth-promoting pathway known to drive cellular transformation and oncogenesis in breast cancers. HER2 amplification is detected in ~20% of all human breast cancer and is quite prevalent (up to 49%) in ductal carcinoma in situ (DCIS). The E3 ubiquitin ligase SIAH is considered a key downstream “gatekeeper” required for proper HER2/EGFR/RAS signal transduction. Formalin-fixed, paraffin-embedded resection specimens from 65 patients with DCIS treated with wide excision only were stained with an anti-SIAH antibody, and the percentage of tumor and normal adjacent tissue cells positive for SIAH nuclear staining were recorded. Statistical analysis was performed comparing SIAH staining in tumor cells to disease recurrence, histologic type, necrosis, hormone receptor status, and Her2/neu status, as well as nuclear grade. Correlation of SIAH expression in tumor cells with SIAH expression in normal adjacent tissue and age was also examined. Expression levels of SIAH in tumor cells was significantly higher in specimens from patients with recurrence (median = 19%) as compared to patients without recurrence (7%) (P < 0.001). There was also significantly increased SIAH expression in tumors with more aggressive features including comedo morphology (13.5% in comedo vs. 7% in other histologic types, P = 0.014). No significant association was observed between SIAH expression and estrogen receptor, progesterone receptor, and Her2/neu status. There was a significant correlation between SIAH expression in tumors and normal adjacent tissue (Spearman correlation = 0.58, P < 0.001) as well as between SIAH expression in normal adjacent tissue and patient age (Spearman correlation = −0.59, P < 0.001). No significant correlation was identified between patient age and SIAH expression in tumors (Spearman correlation = −0.23, P = 0.067). In conclusion, SIAH may represent a useful prognostic biomarker that predicts DCIS progression to invasive breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249

    Article  PubMed  Google Scholar 

  2. Virnig BA, Tuttle TM, Shamliya T, Kane RL (2010) Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst 102:170–178

    Article  PubMed  Google Scholar 

  3. Sakorafas GH, Farley DR, Peros G (2008) Recent advances and current controversies in the management of DCIS of the breast. Cancer Treat Rev 34(6):483–497

    Article  PubMed  CAS  Google Scholar 

  4. Valenzuela M, Julian TB (2007) Ductal carcinoma in situ: biology, diagnosis, and new therapies. Clin Breast Cancer 7:676–681

    Article  PubMed  CAS  Google Scholar 

  5. Sanders ME, Schuyler PA, Dupont WD, Page DL (2005) The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer 103(12):2481–2484

    Article  PubMed  Google Scholar 

  6. Carthew RW, Rubin GM (1990) Seven in absentia, a gene required for specification of R7 cell fate in the Drosophila eye. Cell 63:561–577

    Article  PubMed  CAS  Google Scholar 

  7. Tang AH, Neufeld TP, Kwan E, Rubin GM (1997) PHYL acts to down-regulate TTK88, a transcriptional repressor of neuronal cell fates, by a SINA-dependent mechanism. Cell 90:459–467

    Article  PubMed  CAS  Google Scholar 

  8. House CM, Möller A, Bowtell DD (2009) Siah proteins: novel drug targets in the Ras and hypoxia pathways. Cancer Res 69(23):8835–8838

    Article  PubMed  CAS  Google Scholar 

  9. Schmidt RL, Park CH, Ahmed AU, Gundelach JH, Reed NR, Cheng S, Knudsen BE, Tang AH (2007) Inhibition of RAS-mediated transformation and tumorigenesis by targeting the downstream E3 ubiquitin ligase seven in absentia homologue. Cancer Res 67(24):11798–11810

    Article  PubMed  CAS  Google Scholar 

  10. Ahmed AU, Schmidt RL, Park CH, Reed NR, Hesse SE, Thomas CF, Molina JR, Deschamps C, Yang P, Aubry MC, Tang AH (2008) Effect of disrupting seven-in-absentia homolog 2 function on lung cancer cell growth. J Natl Cancer Inst 100(22):1606–1629

    Article  PubMed  CAS  Google Scholar 

  11. Palmieri D, Fitzgerald D, Shreeve SM, Hua E, Bronder JL, Weil RJ, Davis S, Stark AM, Merino MJ, Kurek R, Mehdom HM, Davis G, Steinberg SM, Meltzer PS, Aldape K, Steeq PS (2009) Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. Mol Cancer Res 7(9):1438–1445

    Article  PubMed  CAS  Google Scholar 

  12. Roh MS, Hong SH, Jeong JS, Kwon HC, Kim MC, Cho SH, Yoon JH, Hwang TH (2004) Gene expression profiling of breast cancers with emphasis of beta-catenin regulation. J Korean Med Sci 19(2):275–282

    Article  PubMed  CAS  Google Scholar 

  13. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23(36):9067–9072

    Article  PubMed  Google Scholar 

  14. Collins LC, Achacoso N, Nekhlyudov L, Fletcher SW, Haque R, Quesenberry CP Jr, Puligandla B, Alshak NS, Goldstein LC, Gown AM, Schnitt SJ, Habel LA (2009) Relationship between clinical and pathologic features of ductal carcinoma in situ and patient age: an analysis of 657 patients. Am J Surg Pathol 33(12):1802–1808

    Article  PubMed  Google Scholar 

  15. Rodrigues NA, Dillon D, Carter D, Parisot N, Haffty BG (2003) Differences in the pathologic and molecular features of intraductal breast carcinoma between younger and older women. Cancer 97(6):1393–1403

    Article  PubMed  Google Scholar 

  16. Cornfield DB, Palazzo JP, Schwartz GF, Goonewardene SA, Kovatich AJ, Chervoneva I, Hyslop T, Schwarting R (2004) The prognostic significance of multiple morphologic features and biologic markers in ductal carcinoma in situ of the breast: a study of a large cohort of patients treated with surgery alone. Cancer 100(11):2317–2327

    Article  PubMed  Google Scholar 

  17. Hosmer DW, Lemeshow S (2000) Applied logistic regression, 2nd edn. Wiley, New York, pp 346–347

  18. Peduzzi PN, Concato J, Kemper E, Holford TR, Feinstein A (1996) A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 99:1373–1379

    Article  Google Scholar 

  19. Tsikitis VL, Chung MA (2006) Biology of ductal carcinoma in situ classification based on biologic potential. Am J Clin Oncol 29(3):305–310

    Article  PubMed  Google Scholar 

  20. Ding L, Kleer CG (2006) Enhancer of Zeste 2 as a marker of preneoplastic progression in the breast. Cancer Res 66(19):9352–9355

    Article  PubMed  CAS  Google Scholar 

  21. Ding L, Erdmann C, Chinnaiyan AM, Merajver SD, Kleer CG (2006) Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues. Cancer Res 66(8):4095–4099

    Article  PubMed  CAS  Google Scholar 

  22. Chen DT, Nasir A, Culhane A, Venkataramu C, Fulp W, Rubio R, Wang T, Agrawal D, McCarthy SM, Gruidl M, Bloom G, Anderson T, White J, Quackenbush J, Yeatman T (2010) Proliferative genes dominate malignancy-risk gene signature in histologically-normal breast tissue. Breast Cancer Res Treat 119(2):335–346

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

A.K.W. was supported by the Susan G. Komen Career Catalyst Grant.

Author information

Authors and Affiliations

  1. Department of Pathology, Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, PA, 19107, USA

    Kathryn C. Behling, Sameep Kadakia & Agnieszka K. Witkiewicz

  2. Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, PA, 19107, USA

    Boris Freydin & Inna Chervoneva

  3. Department of Surgery, Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, PA, 19107, USA

    Gordon F. Schwartz

  4. Department of Cancer Biology, Thomas Jefferson University and Kimmel Cancer Center, Philadelphia, PA, 19107, USA

    Hallgeir Rui

  5. Departments of Surgery and Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN, USA

    Amy Tang

Authors
  1. Kathryn C. Behling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amy Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Boris Freydin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Inna Chervoneva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sameep Kadakia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gordon F. Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hallgeir Rui
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Agnieszka K. Witkiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathryn C. Behling.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Behling, K.C., Tang, A., Freydin, B. et al. Increased SIAH expression predicts ductal carcinoma in situ (DCIS) progression to invasive carcinoma. Breast Cancer Res Treat 129, 717–724 (2011). https://doi.org/10.1007/s10549-010-1254-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-010-1254-8

Keywords

Search

Navigation