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Progesterone receptor A predominance is a discriminator of benefit from endocrine therapy in the ATAC trial

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Abstract

Progesterone receptor (PR) function, while essential in normal human breast, is also implicated in breast cancer risk. The two progesterone receptors, PRA and PRB, are co-expressed at equivalent levels in normal breast, but early in carcinogenesis normal levels of PRA:PRB are frequently disrupted, and predominance of one isoform, usually PRA, results. In model systems, PRA and PRB have different activities, and altering the PRA:PRB ratio in cell lines alters PR signaling. The purpose of this study was to determine whether hormonal or reproductive factors contribute to imbalanced PRA:PRB expression in breast tumors and the impact of PRA:PRB imbalance on disease outcome. The relative expression of PRA and PRB proteins was determined by dual immunofluorescence histochemistry in archival breast tumors and associations with clinical and reproductive history assessed. PRA:PRB expression was not influenced by reproductive factors, whereas exogenous hormone use (menopausal hormone treatment, MHT) favored PRB expression (p < 0.035). The PRA:PRB ratio may be a discriminator of response to endocrine therapy in the TransATAC sample collection, with high PRA:PRB ratio predicting earlier relapse for women on tamoxifen, but not anastrozole (mean lnPRA:PRB ratio; HR (95 % CI) tamoxifen 2.45 (1.20–4.99); p value 0.02; anastrozole 0.80 (0.36–1.78); p value 0.60). The results of this study show that PRA:PRB imbalance in breast cancers is not associated with lifetime endogenous endocrine and reproductive factors, but is associated with MHT use, and that PRA predominance can discriminate those women who will relapse earlier on tamoxifen treatment. These data support a role for imbalanced PRA:PRB expression in breast cancer progression and relative benefit from endocrine treatment.

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References

  1. Santen RJ (2003) Risk of breast cancer with progestins: critical assessment of current data. Steroids 68(10–13):953–964. doi:10.1016/S0039-128X(03)00138-7

    Article  CAS  PubMed  Google Scholar 

  2. Persson I (2000) Estrogens in the causation of breast, endometrial and ovarian cancers—evidence and hypotheses from epidemiological findings. J Steroid Biochem Mol Biol 74(5):357–364

    Article  CAS  PubMed  Google Scholar 

  3. Brisken C (2013) Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nat Rev Cancer 13(6):385–396. doi:10.1038/nrc3518

    Article  CAS  PubMed  Google Scholar 

  4. Chlebowski RT, Kuller LH, Prentice RL, Stefanick ML, Manson JE, Gass M, Aragaki AK, Ockene JK, Lane DS, Sarto GE, Rajkovic A, Schenken R, Hendrix SL, Ravdin PM, Rohan TE, Yasmeen S, Anderson G (2009) Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med 360(6):573–587. doi:10.1056/NEJMoa0807684

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Mote PA, Balleine RL, McGowan EM, Clarke CL (1999) Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle. J Clin Endocrinol Metab 84(8):2963–2971

    CAS  PubMed  Google Scholar 

  6. Mote PA, Bartow S, Tran N, Clarke CL (2002) Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res Treat 72(2):163–172

    Article  CAS  PubMed  Google Scholar 

  7. Chou YC, Uehara N, Lowry JR, Shyamala G (2003) Mammary epithelial cells of PR-A transgenic mice exhibit distinct alterations in gene expression and growth potential associated with transformation. Carcinogenesis 24(3):403–409

    Article  CAS  PubMed  Google Scholar 

  8. Fleisch MC, Chou YC, Cardiff RD, Asaithambi A, Shyamala G (2009) Overexpression of progesterone receptor A isoform in mice leads to endometrial hyperproliferation, hyperplasia and atypia. Mol Hum Reprod 15(4):241–249. doi:10.1093/molehr/gap013

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. McGowan EM, Saad S, Bendall LJ, Bradstock KF, Clarke CL (2004) Effect of progesterone receptor A predominance on breast cancer cell migration into bone marrow fibroblasts. Breast Cancer Res Treat 83(3):211–220

    Article  CAS  PubMed  Google Scholar 

  10. Hopp TA, Weiss HL, Hilsenbeck SG, Cui Y, Allred DC, Horwitz KB, Fuqua SA (2004) Breast cancer patients with progesterone receptor PR-A-rich tumors have poorer disease-free survival rates. Clin Cancer Res 10(8):2751–2760

    Article  CAS  PubMed  Google Scholar 

  11. Early Breast Cancer Trialists’ Collaborative Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687–1717

    Article  Google Scholar 

  12. Saphner T, Tormey DC, Gray R (1996) Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14(10):2738–2746

    CAS  PubMed  Google Scholar 

  13. Dowsett M, Allred C, Knox J, Quinn E, Salter J, Wale C, Cuzick J, Houghton J, Williams N, Mallon E, Bishop H, Ellis I, Larsimont D, Sasano H, Carder P, Cussac AL, Knox F, Speirs V, Forbes J, Buzdar A (2008) Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J Clin Oncol 26(7):1059–1065. doi:10.1200/JCO.2007.12.9437

    Article  CAS  PubMed  Google Scholar 

  14. Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF, ATAC/LATTE investigators (2010) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 11(12):1135–1141. doi:10.1016/S1470-2045(10)70257-6

    Article  CAS  PubMed  Google Scholar 

  15. Buzdar A, Chlebowski R, Cuzick J, Duffy S, Forbes J, Jonat W, Ravdin P (2006) Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer. Curr Med Res Opin 22(8):1575–1585. doi:10.1185/030079906X120940

    Article  CAS  PubMed  Google Scholar 

  16. Dowsett M (2004) Biomarker investigations from the ATAC trial: the role of TA01. Breast Cancer Res Treat 87(Suppl 1):S11–S18. doi:10.1007/s10549-004-1578-3

    Article  CAS  PubMed  Google Scholar 

  17. Clarke CL, Zaino RJ, Feil PD, Miller JV, Steck ME, Ohlsson-Wilhelm BM, Satyaswaroop PG (1987) Monoclonal antibodies to human progesterone receptor: characterization by biochemical and immunohistochemical techniques. Endocrinology 121(3):1123–1132. doi:10.1210/endo-121-3-1123

    Article  CAS  PubMed  Google Scholar 

  18. Mote PA, Johnston JF, Manninen T, Tuohimaa P, Clarke CL (2001) Detection of progesterone receptor forms A and B by immunohistochemical analysis. J Clin Pathol 54(8):624–630

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Khushi M, Edwards G, de Marcos DA, Carpenter JE, Graham JD, Clarke CL (2013) Open source tools for management and archiving of digital microscopy data to allow integration with patient pathology and treatment information. Diagn Pathol 8:22. doi:10.1186/1746-1596-8-22

    Article  PubMed Central  PubMed  Google Scholar 

  20. Graham JD, Yeates C, Balleine RL, Harvey SS, Milliken JS, Bilous AM, Clarke CL (1995) Characterization of progesterone receptor A and B expression in human breast cancer. Cancer Res 55(21):5063–5068

    CAS  PubMed  Google Scholar 

  21. Hilton HN, Doan TB, Graham JD, Oakes SR, Silvestri A, Santucci N, Kantimm S, Huschtscha LI, Ormandy CJ, Funder JW, Simpson ER, Kuczek ES, Leedman PJ, Tilley WD, Fuller PJ, Muscat GE, Clarke CL (2014) Acquired convergence of hormone signaling in breast cancer: ER and PR transition from functionally distinct in normal breast to predictors of metastatic disease. Oncotarget 5(18):8651–8664

    PubMed Central  PubMed  Google Scholar 

  22. Isaksson E, Wang H, Sahlin L, von Schoultz B, Cline JM, von Schoultz E (2003) Effects of long-term HRT and tamoxifen on the expression of progesterone receptors A and B in breast tissue from surgically postmenopausal cynomolgus macaques. Breast Cancer Res Treat 79(2):233–239

    Article  CAS  PubMed  Google Scholar 

  23. Lind T, Cameron EH, Hunter WM (1978) Serum prolactin, gonadotrophin and oestrogen levels in women receiving hormone replacement therapy. Br J Obstet Gynaecol 85(2):138–141

    Article  CAS  PubMed  Google Scholar 

  24. Graham JD, Roman SD, McGowan E, Sutherland RL, Clarke CL (1995) Preferential stimulation of human progesterone receptor B expression by estrogen in T-47D human breast cancer cells. J Biol Chem 270(51):30693–30700

    Article  CAS  PubMed  Google Scholar 

  25. Mangal RK, Wiehle RD, Poindexter AN 3rd, Weigel NL (1997) Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle. J Steroid Biochem Mol Biol 63(4–6):195–202

    Article  CAS  PubMed  Google Scholar 

  26. Daling JR, Malone KE, Doody DR, Voigt LF, Bernstein L, Marchbanks PA, Coates RJ, Norman SA, Weiss LK, Ursin G, Burkman RT, Deapen D, Folger SG, McDonald JA, Simon MS, Strom BL, Spirtas R (2003) Association of regimens of hormone replacement therapy to prognostic factors among women diagnosed with breast cancer aged 50–64 years. Cancer Epidemiol Biomark Prev 12(11):1175–1181

    CAS  Google Scholar 

  27. Bundred NJ (2001) Prognostic and predictive factors in breast cancer. Cancer Treat Rev 27(3):137–142. doi:10.1053/ctrv.2000.0207

    Article  CAS  PubMed  Google Scholar 

  28. Mittra I, MacRae KD (1991) A meta-analysis of reported correlations between prognostic factors in breast cancer: does axillary lymph node metastasis represent biology or chronology? Eur J Cancer 27(12):1574–1583

    Article  CAS  PubMed  Google Scholar 

  29. Mohsin SK, Weiss H, Havighurst T, Clark GM, Berardo M, le Roanh D, To TV, Qian Z, Love RR, Allred DC (2004) Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study. Mod Pathol 17(12):1545–1554. doi:10.1038/modpathol.3800229

    Article  CAS  PubMed  Google Scholar 

  30. Colleoni M, Giobbie-Hurder A, Regan MM, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Lang I, Smith I, Chirgwin J, Pienkowski T, Wardley A, Price KN, Gelber RD, Coates AS, Goldhirsch A (2011) Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study. J Clin Oncol 29(9):1117–1124. doi:10.1200/jco.2010.31.6455

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Arpino G, Weiss H, Lee AV, Schiff R, De Placido S, Osborne CK, Elledge RM (2005) Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst 97(17):1254–1261

    Article  CAS  PubMed  Google Scholar 

  32. Osborne CK, Schiff R, Arpino G, Lee AS, Hilsenbeck VG (2005) Endocrine responsiveness: understanding how progesterone receptor can be used to select endocrine therapy. Breast 14(6):458–465

    Article  PubMed  Google Scholar 

  33. Jirstrom K, Stendahl M, Ryden L, Kronblad A, Bendahl PO, Stal O, Landberg G (2005) Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res 65(17):8009–8016. doi:10.1158/0008-5472.CAN-05-0746

    PubMed  Google Scholar 

  34. Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P (1990) Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 9(5):1603–1614

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Graham JD, Yager ML, Hill HD, Byth K, O’Neill GM, Clarke CL (2005) Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells. Mol Endocrinol 19(11):2713–2735

    Article  CAS  PubMed  Google Scholar 

  36. Jacobsen BM, Richer JK, Schittone SA, Horwitz KB (2002) New human breast cancer cells to study progesterone receptor isoform ratio effects and ligand-independent gene regulation. J Biol Chem 277(31):27793–27800. doi:10.1074/jbc.M202584200

    Article  CAS  PubMed  Google Scholar 

  37. Hagan CR, Lange CA (2014) Molecular determinants of context-dependent progesterone receptor action in breast cancer. BMC Med 12:32. doi:10.1186/1741-7015-12-32

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

PAM and CLC were supported by the National Health and Medical Research Council of Australia (107222), and PAM received an award from the Australian Society for Medical Research. HNH is supported by a Postdoctoral Fellowship co-funded by the Cure Cancer Australia Foundation and the National Breast Cancer Foundation. CLC is a research fellow of the National Health and Medical Research Council of Australia.

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Author notes

  1. Anne Gompel

    Present address: Unité de Gynécologie Endocrinienne, Université Paris Descartes, Hopitaux Universitaires Port Royal Cochin, Paris, France

Authors and Affiliations

  1. Centre for Cancer Research, Westmead Millennium Institute, University of Sydney Medical School, Hawkesbury Road, Westmead, NSW, 2145, Australia

    Patricia A. Mote, Chris Howe, Heidi N. Hilton, J. Dinny Graham & Christine L. Clarke

  2. INSERM U1007, Paris, France

    Anne Gompel & Patricia Forgez

  3. Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University London, London, UK

    Ivana Sestak & Jack Cuzick

  4. Academic Department of Biochemistry, Royal Marsden Hospital, London, UK

    Mitch Dowsett

  5. Laboratoire d’Anatomie-Pathologique-AP-HP, Hôpital Hôtel-Dieu de Paris, Université Paris Descartes, Paris, France

    Danielle Hugol

  6. Westmead Millennium Institute, University of Sydney, Westmead, NSW, 2145, Australia

    Karen Byth

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  1. Patricia A. Mote
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Correspondence to Christine L. Clarke.

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Mote, P.A., Gompel, A., Howe, C. et al. Progesterone receptor A predominance is a discriminator of benefit from endocrine therapy in the ATAC trial. Breast Cancer Res Treat 151, 309–318 (2015). https://doi.org/10.1007/s10549-015-3397-0

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  • DOI: https://doi.org/10.1007/s10549-015-3397-0

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