Skip to main content

Advertisement

SpringerLink
Log in

Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients

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

Abstract

The farnesoid X receptor (FXR, NR1H4), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, is normally produced in the liver and the gastrointestinal tract, where it acts as a bile acid sensor. It has been recently detected in breast cancer cell lines and tissue specimens. The expression of FXR was scored (0–8) by immunohistochemistry on 204 breast cancer samples and correlated with established cancer biomarkers. Moreover, the effect of the FXR activator chenodeoxycholic acid (CDCA) was determined on cell proliferation and estrogen receptor regulation/activation in breast cancer cell lines. FXR was detected in 82.4% of samples with a high median expression score of 5. FXR expression significantly correlated with estrogen receptor (ER) expression (P = 0.009) and luminal-like markers. In ER-positive tumors, FXR expression was significantly correlated with the proliferation marker Ki-67 (P < 0.001) and the nodal status (P = 0.028), but only so in postmenopausal women, suggesting that lack of estrogens may disclose the association between FXR and cell proliferation. In vitro experiments confirmed clinical data since CDCA stimulated the proliferation of ER-positive cells only in steroid-free medium, a stimulation inhibited upon siRNA-silencing of FXR expression as well as ER blockade by antiestrogens. Moreover, co-immunoprecipitation experiments revealed that CDCA activated-FXR interacted with ER. These results suggest that ER-positive breast tumors could be stimulated to proliferate via a crosstalk between FXR and ER, particularly in a state of estrogen deprivation (menopause, aromatase inhibitors).

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW et al (1995) Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81:687–693

    Article  PubMed  CAS  Google Scholar 

  2. Wang H, Chen J, Hollister K, Sowers LC, Forman BM (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3:543–553

    Article  PubMed  CAS  Google Scholar 

  3. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1365

    Article  PubMed  CAS  Google Scholar 

  4. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD et al (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365–1368

    Article  PubMed  CAS  Google Scholar 

  5. Modica S, Moschetta A (2006) Nuclear bile acid receptor FXR as pharmacological target: are we there yet? FEBS Lett 580:5492–5499

    Article  PubMed  CAS  Google Scholar 

  6. Lee FY, Lee H, Hubbert ML, Edwards PA, Zhang Y (2006) FXR, a multipurpose nuclear receptor. Trends Biochem Sci 31:572–580

    Article  PubMed  CAS  Google Scholar 

  7. Edwards PA, Kast HR, Anisfeld AM (2002) BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. J Lipid Res 43:2–12

    PubMed  CAS  Google Scholar 

  8. Kalaany NY, Mangelsdorf DJ (2006) LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol 68:159–191

    Article  PubMed  CAS  Google Scholar 

  9. Claudel T, Sturm E, Kuipers F, Staels B (2004) The farnesoid X receptor: a novel drug target? Expert Opin Investig Drugs 13:1135–1148

    Article  PubMed  CAS  Google Scholar 

  10. Westin S, Heyman RA, Martin R (2005) FXR, a therapeutic target for bile acid and lipid disorders. Mini Rev Med Chem 5:719–727

    Article  PubMed  CAS  Google Scholar 

  11. Bishop-Bailey D, Walsh DT, Warner TD (2004) Expression and activation of the farnesoid X receptor in the vasculature. Proc Natl Acad Sci USA 101:3668–3673

    Article  PubMed  CAS  Google Scholar 

  12. He F, Li J, Mu Y, Kuruba R, Ma Z, Wilson A, Alber S, Jiang Y, Stevens T, Watkins S et al (2006) Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells. Circ Res 98:192–199

    Article  PubMed  CAS  Google Scholar 

  13. Silva J, Dasgupta S, Wang G, Krishnamurthy K, Ritter E, Bieberich E (2006) Lipids isolated from bone induce the migration of human breast cancer cells. J Lipid Res 47:724–733

    Article  PubMed  CAS  Google Scholar 

  14. Swales KE, Korbonits M, Carpenter R, Walsh DT, Warner TD, Bishop-Bailey D (2006) The farnesoid X receptor is expressed in breast cancer and regulates apoptosis and aromatase expression. Cancer Res 66:10120–10126

    Article  PubMed  CAS  Google Scholar 

  15. Journe F, Laurent G, Chaboteaux C, Nonclercq D, Durbecq V, Larsimont D, Body JJ (2008) Farnesol, a mevalonate pathway intermediate, stimulates MCF-7 breast cancer cell growth through farnesoid-X-receptor-mediated estrogen receptor activation. Breast Cancer Res Treat 107:49–61

    Article  PubMed  CAS  Google Scholar 

  16. Costarelli V, Sanders TA (2002) Plasma deoxycholic acid concentration is elevated in postmenopausal women with newly diagnosed breast cancer. Eur J Clin Nutr 56:925–927

    Article  PubMed  CAS  Google Scholar 

  17. Raju U, Levitz M, Javitt NB (1990) Bile acids in human breast cyst fluid: the identification of lithocholic acid. J Clin Endocrinol Metab 70:1030–1034

    Article  PubMed  CAS  Google Scholar 

  18. Javitt NB, Budai K, Miller DG, Cahan AC, Raju U, Levitz M (1994) Breast-gut connection: origin of chenodeoxycholic acid in breast cyst fluid. Lancet 343:633–635

    Article  PubMed  CAS  Google Scholar 

  19. Costarelli V, Sanders TA (2002) Plasma bile acids and risk of breast cancer. IARC Sci Publ 156:305–306

    PubMed  CAS  Google Scholar 

  20. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235

    Article  PubMed  Google Scholar 

  21. Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168

    PubMed  CAS  Google Scholar 

  22. Colozza M, Azambuja E, Cardoso F, Sotiriou C, Larsimont D, Piccart MJ (2005) Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? Ann Oncol 16:1723–1739

    Article  PubMed  CAS  Google Scholar 

  23. Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL (1997) Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem 272:10882–10894

    Article  PubMed  CAS  Google Scholar 

  24. Foster JS, Henley DC, Bukovsky A, Seth P, Wimalasena J (2001) Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function. Mol Cell Biol 21:794–810

    Article  PubMed  CAS  Google Scholar 

  25. Sherr CJ, Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9:1149–1163

    Article  PubMed  CAS  Google Scholar 

  26. De Gottardi A, Touri F, Maurer CA, Perez A, Maurhofer O, Ventre G, Bentzen CL, Niesor EJ, Dufour JF (2004) The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer. Dig Dis Sci 49:982–989

    Article  PubMed  Google Scholar 

  27. De Gottardi A, Dumonceau JM, Bruttin F, Vonlaufen A, Morard I, Spahr L, Rubbia-Brandt L, Frossard JL, Dinjens WN, Rabinovitch PS et al (2006) Expression of the bile acid receptor FXR in Barrett’s esophagus and enhancement of apoptosis by guggulsterone in vitro. Mol Cancer 5:48

    Article  PubMed  CAS  Google Scholar 

  28. Shishodia S, Aggarwal BB (2004) Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. J Biol Chem 279:47148–47158

    Article  PubMed  CAS  Google Scholar 

  29. Fredersdorf S, Burns J, Milne AM, Packham G, Fallis L, Gillett CE, Royds JA, Peston D, Hall PA, Hanby AM et al (1997) High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip1) and degree of malignancy in human breast and colorectal cancers. Proc Natl Acad Sci USA 94:6380–6385

    Article  PubMed  CAS  Google Scholar 

  30. Sweeney KJ, Swarbrick A, Sutherland RL, Musgrove EA (1998) Lack of relationship between CDK activity and G1 cyclin expression in breast cancer cells. Oncogene 16:2865–2878

    Article  PubMed  CAS  Google Scholar 

  31. Hui R, Cornish AL, McClelland RA, Robertson JF, Blamey RW, Musgrove EA, Nicholson RI, Sutherland RL (1996) Cyclin D1 and estrogen receptor messenger RNA levels are positively correlated in primary breast cancer. Clin Cancer Res 2:923–928

    PubMed  CAS  Google Scholar 

  32. Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L et al (1997) Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med 3:227–230

    Article  PubMed  CAS  Google Scholar 

  33. Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677

    Article  PubMed  CAS  Google Scholar 

  34. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512

    Article  PubMed  CAS  Google Scholar 

  35. Mateyak MK, Obaya AJ, Sedivy JM (1999) c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol Cell Biol 19:4672–4683

    PubMed  CAS  Google Scholar 

  36. Brodie AM, Njar VC (2000) Aromatase inhibitors and their application in breast cancer treatment*. Steroids 65:171–179

    Article  PubMed  CAS  Google Scholar 

  37. Blankenstein MA, van de Ven J, Maitimu-Smeele I, Donker GH, de Jong PC, Daroszewski J, Szymczak J, Milewicz A, Thijssen JH (1999) Intratumoral levels of estrogens in breast cancer. J Steroid Biochem Mol Biol 69:293–297

    Article  PubMed  CAS  Google Scholar 

  38. Nagengast FM, Grubben MJ, van Munster IP (1995) Role of bile acids in colorectal carcinogenesis. Eur J Cancer 31A:1067–1070

    Article  PubMed  CAS  Google Scholar 

  39. Lewis SJ, Heaton KW (1999) The metabolic consequences of slow colonic transit. Am J Gastroenterol 94:2010–2016

    Article  PubMed  CAS  Google Scholar 

  40. Carmichael AR (2006) Obesity as a risk factor for development and poor prognosis of breast cancer. BJOG 113:1160–1166

    Article  PubMed  CAS  Google Scholar 

  41. Halmy L, Feher T, Steczek K, Farkas A (1986) High serum bile acid level in obesity: its decrease during and after total fasting. Acta Med Hung 43:55–58

    PubMed  CAS  Google Scholar 

  42. Cho E, Spiegelman D, Hunter DJ, Chen WY, Stampfer MJ, Colditz GA, Willett WC (2003) Premenopausal fat intake and risk of breast cancer. J Natl Cancer Inst 95:1079–1085

    Article  PubMed  Google Scholar 

  43. Costarelli V, Sanders TA (2001) Acute effects of dietary fat composition on postprandial plasma bile acid and cholecystokinin concentrations in healthy premenopausal women. Br J Nutr 86:471–477

    Article  PubMed  CAS  Google Scholar 

  44. Harlan LC, Coates RJ, Block G, Greenberg RS, Ershow A, Forman M, Austin DF, Chen V, Heymsfield SB (1993) Estrogen receptor status and dietary intakes in breast cancer patients. Epidemiology 4:25–31

    Article  PubMed  CAS  Google Scholar 

  45. Kushi LH, Potter JD, Bostick RM, Drinkard CR, Sellers TA, Gapstur SM, Cerhan JR, Folsom AR (1995) Dietary fat and risk of breast cancer according to hormone receptor status. Cancer Epidemiol Biomarkers Prev 4:11–19

    PubMed  CAS  Google Scholar 

  46. Jain M, Miller AB (1997) Tumor characteristics and survival of breast cancer patients in relation to premorbid diet and body size. Breast Cancer Res Treat 42:43–55

    Article  PubMed  CAS  Google Scholar 

  47. Journe F, Durbecq V, Chaboteaux C, Rouas G, IdBoufker H, Laurent G, Larsimont D, Body J (2008) Farnesoid X receptor in primary breast carcinoma: a new marker to predict bone metastasis? Bone 42(Suppl 1):S97 (abstract 175)

Download references

Acknowledgements

This study received financial support from the “Fondation Medic”, from the “Fondation contre le Cancer”, from the Belgian Fund for Medical Scientific Research (grants no. 3.4512.03 and 3.4501.08), from the “Fondation Lambeau-Marteaux”, and from “Les Amis de l’Institut Bordet”. Virginie Durbecq, Christos Sotiriou and Guy Laurent are respectively Scientific Research Worker, Research Associate and Senior Research Associate of the National Fund for Scientific Research (Belgium).

Author information

Authors and Affiliations

  1. Laboratory of Endocrinology & Translational Research Unit, Department of Internal Medicine, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium

    Fabrice Journe, Virginie Durbecq, Carole Chaboteaux, Ghizlane Rouas, Christos Sotiriou, Jean-Jacques Body & Denis Larsimont

  2. Laboratory of Endocrinology and Bone Diseases, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1 rue Héger-Bordet, 1000, Brussels, Belgium

    Fabrice Journe

  3. Laboratory of Histology, Faculty of Medicine and Pharmacy, Université de Mons-Hainaut (UMH), Mons, Belgium

    Guy Laurent & Denis Nonclercq

Authors
  1. Fabrice Journe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Virginie Durbecq
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carole Chaboteaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ghizlane Rouas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guy Laurent
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Denis Nonclercq
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christos Sotiriou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Jacques Body
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Denis Larsimont
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fabrice Journe.

Additional information

Fabrice Journe and Virginie Durbecq had contributed equally to this work and should be considered as joint first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Journe, F., Durbecq, V., Chaboteaux, C. et al. Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients. Breast Cancer Res Treat 115, 523–535 (2009). https://doi.org/10.1007/s10549-008-0094-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-008-0094-2

Keywords

Search

Navigation