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Differences in expression of proliferation-associated genes and RANKL across the menstrual cycle in estrogen receptor-positive primary breast cancer

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An Erratum to this article was published on 26 November 2014

Abstract

The purpose of this study is to determine if there are differences in the expression of estrogen-regulated genes (ERGs), proliferation-associated genes and the progesterone effector RANKL, in premenopausal ER+ breast cancer as a result of the major changes in hormone levels that occur through the menstrual cycle. Primary ER+ tumours from 174 patients were assigned to one of three menstrual cycle windows: W1 (days 27–35 + 1–6), W2 (days 7–16) and W3 (days 17–26). RNA expression of 42 genes, including 24 putative genes associated with plasma E2 levels, seven proliferation genes and RANKL was measured. Expression of PGR, TFF1, GREB1 and PDZK1 followed the previously reported pattern: a higher level in W2 compared to W1 while W3 had an intermediate value, mirroring changes in plasma estradiol. Of the other 20 ERGs, four (RUNX1, AGR2, SERPINA3 and SERPINA5) showed significant differences (p = 0.009–0.049) in expression across the menstrual cycle. The expression of six of seven proliferation-associated genes varied across the cycle but differently from the ERGs, being 20–35 % lower in W3 compared to W1 and W2 (p = 0.004–0.031). Expression of RANKL was 2.5 to 3-fold highest in W3 (p = 0.0001) and negatively correlated to the expression of the proliferation-associated genes (r = −0.37; p < 0.0001). Expression of proliferation-associated genes and RANKL in ER+ breast tumours varies across the menstrual cycle showing a different rhythm to that of ERGs. This may affect the interpretation of gene expression profiles but may be exploitable as an endogenous test of endocrine responsiveness.

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Abbreviations

ER:

Estrogen receptor

GnRH:

Gonadotrophin-releasing hormone

PgR:

Progesterone receptor

E2:

Estradiol

ERG:

Estrogen-regulated gene

AvERG:

Average estrogen-regulated genes

LMP:

Last menstrual period

qPCR:

Quantitative real-time polymerase chain reaction

IHC:

Immunohistochemistry

SHBG:

Sex hormone binding globulin

References

  1. Brinton LA, Sherman ME, Carreon JD et al (2008) Recent trends in breast cancer among younger women in the United States. J Natl Cancer Inst 100:1643–1648

    Article  PubMed Central  PubMed  Google Scholar 

  2. Smith I, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer J-U, Ashley SE, Francis S, Boeddinghaus I, Walsh G, IMPACT Trialists Group (2005) Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, Tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen or Combined with Tamoxifen (IMPACT) multicentre double-blind randomized trial. J Clin Oncol 23:5108–5116

    Article  CAS  PubMed  Google Scholar 

  3. Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, A’Hern R, Salter J, Detre S, Hills M, Walsh G (2007) Prognostic value of Ki67 Expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst 99:167–170

    Article  CAS  PubMed  Google Scholar 

  4. Ellis MJ, Tao Y, Luo J, A’Hern R, Evans DB, Bhatnagar AS, Chaudri Ross HA, von Kameke A, Miller WR, Smith I, Eiermann W, Dowsett M (2008) Outcome prediction for estrogen receptor-positive breast cancer based on post-neoadjuvant endocrine tumour characteristics. J Natl Cancer Inst 100:1380–1388

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Freedman OC, Amir E, Hanna W, Kahn H, O’Malley F, Dranitsaris G, Cole DE, Verma S, Folkerd E, Dowsett M, Clemons M (2010) A randomized trail exploring the biomarker effects of neoadjuvant sequential treatment with exemestane and anastrozole in post-menopausal women with hormone receptor-positive breast cancer. Breast Cancer Res Treat 119:155–161

    Article  CAS  PubMed  Google Scholar 

  6. Klijn JG, Beex LV, Mauriac L, van Zijl JA, Veyret C, Wildiers J, Jassem J, Piccart M, Burghouts J, Becquart D, Seynaeve C, Mignolet F, Duchateau L (2000) Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 92:903–911

    Article  CAS  PubMed  Google Scholar 

  7. Jannuzzo MG, Di Salle E, Spinelli R, Pirotta N, Buchan P, Bello A (2009) Estrogen suppression in premenopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone. Breast Cancer Res Treat 11:491–499

    Article  Google Scholar 

  8. Dunbier AK, Anderson H, Ghazoui Z, Folkerd EJ, A’hern R, Crowder RJ, Hoog J, Smith IE, Osin P, Nerurkar A, Parker JS, Perou CM, Ellis MJ, Dowsett M (2010) Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women. J Clin Oncol 28:1161–1167

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Haynes BP, Viale G, Galimberti V, Rotmensz N, Gibelli B, A’Hern R, Smith IE, Dowsett M (2013) Expression of key oestrogen-regulated genes differs substantially across the menstrual cycle in oestrogen receptor-positive primary breast cancer. Breast Cancer Res Treat 138:157–165

    Article  CAS  PubMed  Google Scholar 

  10. Dunbier AK, Ghazoui Z, Anderson H, Salter J, Nerurkar A, Osin P, A’hern R, Miller WR, Smith IE, Dowsett M (2013) Molecular profiling of aromatase inhibitor-treated postmenopausal breast tumors identifies immune-related correlates of resistance. Clin Cancer Res 19:2775–2786

    Article  CAS  PubMed  Google Scholar 

  11. Tanos T, Sflomos G, Echeverria PC, Ayyanan A, Gutierrez M, Delaloye JF, Raffoul W, Fiche M, Dougall W, Schneider P, Yalcin-Ozuysal O, Brisken C (2013) Progesterone/RANKL is a major regulatory axis in the human breast. Sci Transl Med 5:182ra55

    Article  PubMed  Google Scholar 

  12. Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D, Dougall WC (2010) RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468(7320):103–107

    Article  CAS  PubMed  Google Scholar 

  13. Zurrida S, Galimberti V, Gibelli B, Luini A, Gianoglio S, Sandri MT, Passerini R, Maisonneuve P, Zucali P, Jeronesi G, Pigatto F, Veronesi U (2001) Timing of breast cancer surgery in relation to the menstrual cycle: an update of developments. Crit Rev Oncol Hematol 38:223–230

    Article  CAS  PubMed  Google Scholar 

  14. Weigel MT, Ghazoui Z, Dunbier A, Pancholi S, Dowsett M, Martin LA (2012) Preclinical and clinical studies of estrogen deprivation support the PDGF/Abl pathway as a novel therapeutic target for overcoming endocrine resistance in breast cancer. Breast Cancer Res 14:R78

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826

    Article  CAS  PubMed  Google Scholar 

  16. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27:1160–1167

    Article  PubMed Central  PubMed  Google Scholar 

  17. Bastien RR, Rodríguez-Lescure Á, Ebbert MT, Prat A, Munárriz B, Rowe L, Miller P, Ruiz-Borrego M, Anderson D, Lyons B, Álvarez I, Dowell T, Wall D, Seguí MÁ, Barley L, Boucher KM, Alba E, Pappas L, Davis CA, Aranda I, Fauron C, Stijleman IJ, Palacios J, Antón A, Carrasco E, Caballero R, Ellis MJ, Nielsen TO, Perou CM, Astill M, Bernard PS, Martín M (2012) PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers. BMC Med Genomics 5:44

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, Fell HP, Ferree S, George RD, Grogan T, James JJ, Maysuria M, Mitton JD, Oliveri P, Osborn JL, Peng T, Ratcliffe AL, Webster PJ, Davidson EH, Hood L, Dimitrov K (2008) Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol 26:317–325

    Article  CAS  PubMed  Google Scholar 

  19. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784–2795

    Article  PubMed Central  PubMed  Google Scholar 

  20. Kadota M, Yang HH, Gomez B et al (2010) Delineating genetic alterations for tumor progression in the MCF10A series of breast cancer cell lines. PLoS One 5:e9201

    Article  PubMed Central  PubMed  Google Scholar 

  21. Wang L, Brugge JS, Janes KA (2011) Intersection of FOXO- and RUNX1-mediated gene expression programs in single breast epithelial cells during morphogenesis and tumor progression. Proc Natl Acad Sci USA 108:E803–E812

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Jo M, Curry TE Jr (2006) Luteinizing hormone-induced RUNX1 regulates the expression of genes in granulosa cells of rat periovulatory follicles. Mol Endocrinol 20:2156–2172

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Anderson E, Clarke RB (2004) Steroid receptors and cell cycle in normal mammary epithelium. J Mammary Gland Biol Neoplasia 9:3–13

    Article  PubMed  Google Scholar 

  24. van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rutgers ET, Friend SH, Bernards R (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009

    Article  PubMed  Google Scholar 

  25. Hu H, Wang J, Gupta A, Shidfar A, Branstetter D, Lee O, Ivancic D, Sullivan M, Chatterton RT Jr, Dougall WC, Khan SA (2014) RANKL expression in normal and malignant breast tissue responds to progesterone and is up-regulated during the luteal phase. Breast Cancer Res Treat 146:515–523

    Article  CAS  PubMed  Google Scholar 

  26. Hosoda M, Yamamoto M, Nakano K, Hatanaka KC, Takakuwa E, Hatanaka Y, Matsuno Y, Yamashita H (2014) Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer. Breast Cancer Res Treat 144:249–261

    Article  CAS  PubMed  Google Scholar 

  27. Owen S, Ye L, Sanders AJ, Mason MD, Jiang WG (2013) Expression profile of receptor activator of nuclear-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) in breast cancer. Anticancer Res 33:199–206

    CAS  PubMed  Google Scholar 

  28. Pfitzner BM, Branstetter D, Loibl S, Denkert C, Lederer B, Schmitt WD, Dombrowski F, Werner M, Rüdiger T, Dougall WC, von Minckwitz G (2014) RANK expression as a prognostic and predictive marker in breast cancer. Breast Cancer Res Treat 145:307–315

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a Grant from the Breast Cancer Research Foundation (IES, MD). We acknowledge support from the National Institute for Health Research RM/ICR Biomedical Research Centre. The Royal Marsden Hospital acknowledges the support of the National Institute for Health Research, through the National Cancer Research Network.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Academic Biochemistry, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK

    Ben P. Haynes & Mitch Dowsett

  2. The Breakthrough Breast Cancer Centre, The Institute of Cancer Research, Fulham Road, London, UK

    Mitch Dowsett

  3. University of Milan School of Medicine, Milan, Italy

    Giuseppe Viale

  4. Division of Pathology, European Institute of Oncology, Milan, Italy

    Giuseppe Viale

  5. Division of Senology, European Institute of Oncology, Milan, Italy

    Viviana Galimberti

  6. Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy

    Nicole Rotmensz

  7. Department of Head & Neck Surgery, European Institute of Oncology, Milan, Italy

    Bianca Gibelli

  8. Department of Medicine, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK

    Ian E. Smith

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  1. Ben P. Haynes
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  2. Giuseppe Viale
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  3. Viviana Galimberti
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  4. Nicole Rotmensz
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  7. Mitch Dowsett
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Corresponding author

Correspondence to Ben P. Haynes.

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Haynes, B.P., Viale, G., Galimberti, V. et al. Differences in expression of proliferation-associated genes and RANKL across the menstrual cycle in estrogen receptor-positive primary breast cancer. Breast Cancer Res Treat 148, 327–335 (2014). https://doi.org/10.1007/s10549-014-3181-6

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  • DOI: https://doi.org/10.1007/s10549-014-3181-6

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