Advertisement

The action of estrogens and progestogens in the young female breast

  • Irene Zolfaroli
    Affiliations
    Service of Obstetrics and Gynecology, Hospital Clínico Universitario-INCLIVA, Av Blasco Ibáñez 17, 46010 Valencia, Spain
    Search for articles by this author
  • Juan J. Tarín
    Affiliations
    Department of Cellular Biology, Functional Biology and Physical Anthropology, University of Valencia, C/Doctor Moliner, 50, 46100 Burjassot, Spain
    Search for articles by this author
  • Antonio Cano
    Correspondence
    Corresponding author at: Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Av. Blasco Ibáñez, 15, 46010 Valencia, Spain.
    Affiliations
    Service of Obstetrics and Gynecology, Hospital Clínico Universitario-INCLIVA, Av Blasco Ibáñez 17, 46010 Valencia, Spain

    Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Av. Blasco Ibáñez, 15, 46010 Valencia, Spain
    Search for articles by this author

      Abstract

      Evidence from different sources sustains a pro-oncogenic role of hormones, estrogens and progestogens, on the breast. The issue is of interest for young women, who are exposed to the hormonal changes imposed by the ovarian cycle and, often, take hormones with contraceptive purposes.
      Experimental and clinical studies show that both estrogens and progesterone are involved in mammary development during puberty and lactation, the changes being observed across mammalian species, including humans. Estrogen receptors, and more particularly the alpha isoform, participate in molecular processes of stem cells differentiation and epithelial proliferation through paracrine actions implicating growth factors. Progesterone also contributes through paracrine mechanisms involving one member of the tumor necrosis factor (TNF) family, the receptor activator of nuclear factor κB ligand (RANKL) and its receptor (RANK).
      Epidemiological studies have found that the length of the exposure to endogenous hormones, as determined by an early menarche or a late menopause, is a risk factor for breast cancer. Additional evidence has derived from studies with compounds modulating the estrogen or the progesterone receptors. Selective estrogen receptor modulators (SERM), like tamoxifen, have been shown to decrease the risk of breast cancer in both pre- and post-menopausal women. Aromatase inhibitors, which drastically reduce the levels of circulating estrogens, have reproduced the findings. The selective progesterone receptor modulators (SPRM) have been less investigated and issues concerning safety have arisen.
      These observations have interest for young women. High-risk women may consider the use of SERMs, for example, to reduce their risk. Much more common is the case of women who take hormones for contraception. The goal of the present article is twofold: i) to summarize the actual knowledge of the mechanisms implicating estrogens and progestogens on the risk for breast cancer and ii) to provide rationality for the debate about potential cancer risk of hormonal contraceptives, frequently used by premenopausal women.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      References

        • Collaborative Group on Hormonal Factors in Breast Cancer
        Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies.
        Lancet Oncol. 2012; 13: 1141-1151
        • IARC
        Combined estrogen-progestogen contraceptives and combined estrogen-progestogen menopausal therapy.
        IARC Monogr Eval Carcinog Risks Hum. 2007; 91: 1-528
        • International Agency for Research on Cancer
        Combined estrogen-progestogen contraceptives.
        IARC Monogr Eval Carcinog Risks Hum. 2012; 100A: 283-317
        • Fisher B.
        • Costantino J.P.
        • Wickerham D.L.
        • Redmond C.K.
        • Kavanah M.
        • Cronin W.M.
        • et al.
        Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study.
        J Natl Cancer Inst. 1998; 90: 1371-1388
        • Goss P.E.
        • Ingle J.N.
        • Alés-Martínez J.E.
        • Cheung A.M.
        • Chlebowski R.T.
        • Wactawski-Wende J.
        • et al.
        Exemestane for breast-cancer prevention in postmenopausal women.
        N Engl J Med. 2011; 364: 2381-2391
      1. Zolfaroli I, Tarín JJ, Cano A. Hormonal contraceptives and breast cancer. Clinical data, Eur J Obstet Gynecol Reprod Biol [Epub ahead of print].

        • Beleut M.
        • Rajaram R.D.
        • Caikovski M.
        • Ayyanan A.
        • Germano D.
        • Choi Y.
        • et al.
        Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland.
        Proc Natl Acad Sci U S A. 2010; 107: 2989-2994
        • Nilsson S.
        • Mäkelä S.
        • Treuter E.
        • Tujague M.
        • Thomsen J.
        • Andersson G.
        • et al.
        Mechanisms of estrogen action.
        Physiol Rev. 2001; 81: 1535-1565
        • Petersen O.W.
        • Hoyer P.E.
        • van Deurs B.
        Frequency and distribution of estrogen receptor-positive cells in normal, nonlactating human breast tissue.
        Cancer Res. 1987; 47: 575-5748
        • Perou C.M.
        • Sørlie T.
        • Eisen M.B.
        • van de Rijn M.
        • Jeffrey S.S.
        • Rees C.A.
        • et al.
        Molecular portraits of human breast tumours.
        Nature. 2000; 406: 747-772
        • González Ricarte M.
        • de Castro Pérez A.
        • Tarín J.J.
        • Cano A.
        Progestogens and risk of breast cancer: a link between bone and breast?.
        Gynecol Endocrinol. 2016; 32: 6-8
        • Harrison H.
        • Simões B.M.
        • Rogerson L.
        • Howell S.J.
        • Landberg G.
        • Clarke R.B.
        Oestrogen increases the activity of oestrogen receptor negative breast cancer stem cells through paracrine EGFR and Notch signalling.
        Breast Cancer Res. 2013; 15: R21
        • Joshi P.A.
        • Jackson H.W.
        • Beristain A.G.
        • Di Grappa M.A.
        • Mote P.A.
        • Clarke C.L.
        • et al.
        Progesterone induces adult mammary stem cell expansion.
        Nature. 2010; 465: 803-807
        • González-Suárez E.
        • Jacob A.P.
        • Jones J.
        • Miller R.
        • Roudier-Meyer M.P.
        • Erwert R.
        • et al.
        RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis.
        Nature. 2010; 468: 103-107
        • Key T.J.
        • Appleby P.N.
        • Reeves G.K.
        • Travis R.C.
        • Alberg A.J.
        • Barricarte A.
        • et al.
        Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.
        Lancet Oncol. 2013; 14: 1009-1019
        • Reeves G.K.
        • Beral V.
        • Green J.
        • Gathani T.
        • Bull D.
        • Million Women Study Collaborators
        Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis.
        Lancet Oncol. 2006; 7: 910-918
        • Anderson G.L.
        • Limacher M.
        • Assaf A.R.
        • Bassford T.
        • Beresford S.A.
        • Black H.
        • et al.
        Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.
        JAMA. 2004; 291: 1701-1712
        • Cano A.
        • Hermenegildo C.
        Modulation of the oestrogen receptor: a process with distinct susceptible steps.
        Hum Reprod Update. 2000; 6: 207-211
        • Gemignani M.L.
        • Hetzel D.J.
        Current advances in endocrine therapy options for premenopausal women with hormone receptor positive breast cancer.
        Gynecol Oncol. 2017; 147: 153-157
        • Fisher B.
        • Costantino J.P.
        • Wickerham D.L.
        • Cecchini R.S.
        • Cronin W.M.
        • Robidoux A.
        • et al.
        Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study.
        J Natl Cancer Inst. 2005; 97: 1652-1662
        • Vogel V.G.
        • Costantino J.P.
        • Wickerham D.L.
        • Cronin W.M.
        • Cecchini R.S.
        • Atkins J.N.
        • et al.
        Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.
        JAMA. 2006; 295: 2727-2741
        • Ferguson D.J.
        • Anderson T.J.
        Morphological evaluation of cell turnover in relation to the menstrual cycle in the resting human breast.
        Br J Cancer. 1981; 44: 177-181
        • Hu H.
        • Wang J.
        • Gupta A.
        • Shidfar A.
        • Branstetter D.
        • Lee O.
        • et al.
        RANKL expression in normal and malignant breast tissue responds to progesterone and is up-regulated during the luteal phase.
        Breast Cancer Res Treat. 2014; 146: 515-523
        • Rossouw J.E.
        • Anderson G.L.
        • Prentice R.L.
        • LaCroix A.Z.
        • Kooperberg C.
        • Stefanick M.L.
        • et al.
        Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.
        JAMA. 2002; 288: 321-333
        • Horwitz K.B.
        The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer?.
        Endocr Rev. 1992; 13: 146-163
        • Klijn J.G.
        • Setyono-Han B.
        • Foekens J.A.
        Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer.
        Steroids. 2000; 65: 825-830
        • Nair H.B.
        • Santhamma B.
        • Krishnegowda N.K.
        • Dileep K.V.
        • Nickisch K.J.
        Effects of combination of estradiol with selective progesterone receptor modulators (SPRMs) on human Breast cancer cells in vitro and in vivo.
        PLoS One. 2016; 11: e0151182
        • Robertson J.F.
        • Willsher P.C.
        • Winterbottom L.
        • Blamey R.W.
        • Thorpe S.
        Onapristone, a progesterone receptor antagonist, as first-line therapy in primary breast cancer.
        Eur J Cancer. 1999; 35: 214-218
        • Engman M.
        • Skoog L.
        • Söderqvist G.
        • Gemzell-Danielsson K.
        The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology.
        Hum Reprod. 2008; 23: 2072-2079
        • Jonat W.
        • Bachelot T.
        • Ruhstaller T.
        • Kuss I.
        • Reimann U.
        • Robertson J.F.
        Randomized phase II study of lonaprisan as second-line therapy for progesterone receptor-positive breast cancer.
        Ann Oncol. 2013; 24: 2543-2548
        • Pfitzner B.M.
        • Branstetter D.
        • Loibl S.
        • Denkert C.
        • Lederer B.
        • Schmitt W.D.
        • et al.
        RANK expression as a prognostic and predictive marker in breast cancer.
        Breast Cancer Res Treat. 2014; 145: 307-315
        • Azim Jr, H.A.
        • Peccatori F.A.
        • Brohée S.
        • Branstetter D.
        • Loi S.
        • Viale G.
        • et al.
        RANK-ligand (RANKL) expression in young breast cancer patients and during pregnancy.
        Breast Cancer Res. 2015; 17: 24
        • Yoldi G.
        • Pellegrini P.
        • Trinidad E.M.
        • Cordero A.
        • Gomez-Miragaya J.
        • Serra-Musach J.
        • et al.
        RANK signaling blockade reduces Breast cancer recurrence by inducing tumor cell differentiation.
        Cancer Res. 2016; 76: 5857-5869