Research Article| Volume 49, ISSUE 1, P16-24, September 24, 2004

Steroidal hormones and proliferation, differentiation and apoptosis in breast cells


      The impact of estrogens (E) and progestins (P) on the breast is crucial. Recent epidemiological studies raised a great concern concerning breast cancer risk and hormone replacement therapy (HRT). However, the effects of HRT in breast tissue remain unclear. Biological data predominantly show that P are antiproliferative and proapoptotic at least for normal breast cells. These antiproliferative effects of P are well described at the cellular level. Whereas E2 increases the level of the various cyclins involved in the cell cycle progression and decreases the cyclin kinase inhibitors, p21 and p27, progestins act in an opposite manner. In addition, they both modulate the phosphorylated rate of Rb involved into the S phase progression. Various proteins of the apoptotic cascade are also targets for E2 and P. We showed that bcl-2, p53 and caspase 3 are oppositely modulated by E2 and P in normal and breast cancer cell cultures.
      It is very possible that in vivo the balance between E2/P, the type of P, specific phenotypes could explain increasing risk during HRT, which appears to be mainly a promoter effect on preexisting transformed cells.


      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'


      Subscribe to Maturitas
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047–1059.

        • Shairer C.
        • Lubin J.
        • Troisi R.
        • Sturgeon S.
        • Brinton L.
        • Hoover R.
        Menopausal estrogen and estrogen–progestin replacement therapy and breast cancer risk.
        J Am Med Assoc. 2000; 283: 485-491
      2. WHI. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the women’s health initiative randomized controlled trial. J Am Med Assoc 2002;288:321–33.

      3. WHI. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the women’s health initiative randomized controlled trial. J Am Med Assoc 2004;291:1701–12.

        • Magnusson C.
        • Baron J.A.
        • Correia N.
        • Bergstrom R.
        • Adami H.O.
        • Persson I.
        Breast-cancer risk following long-term oestrogen- and oestrogen–progestin-replacement therapy.
        Int J Cancer. 1999; 81: 339-344
      4. Million women study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419–27.

      5. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer form 54 epidemiological studies. Lancet 1996;347:1713–27.

        • Kaunitz A.M.
        Depot medroxyprogesterone acetate contraception and the risk of breast and gynecologic cancer.
        J Reprod Med. 1996; 41: 419-425
        • Plu-Bureau G.
        • Le M.
        • Sitruk-Ware R.
        • Thalabard J.C.
        • Mauvais-Jarvis P.
        Progestogen use and risk of breast cancer in a cohort study of premenopausal women with benign breast disease.
        Br J Cancer. 1994; 70: 270-277
        • Longacre T.A.
        • Bartow S.A.
        A correlative morphologic study of human breast and endometrium in the menstrual cycle.
        Am J Surg Pathol. 1986; 10: 382-393
        • Going J.J.
        • Anderson T.J.
        • Battersby S.C.
        • Macintyre C.C.A.
        Proliferative and secretory activity in human breast during natural and artificial menstrual cycles.
        Am J Pathol. 1988; 130: 193-204
        • Chang K.J.
        • Fournier S.
        • Lee Ti T.Y.
        • de Lignières B.
        • Linares G.
        Influence of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo.
        Fertil Steril. 1995; 63: 785-791
      6. Foidart JM, Colin C, Denoo X, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril 1998;69:963, 969.

        • Hofset L.J.
        • Raafat A.M.
        • Osuch J.R.
        • Pathak D.R.
        • Slmoski C.A.
        • Haslam S.Z.
        Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postemenopausal breast.
        J Clin Endocrinol Metab. 1999; 84: 4559-4565
        • Hargreaves D.F.
        • Knox F.
        • Swindell R.
        • Potten C.S.
        • Bundred N.J.
        Epithelial proliferation and hormone receptor status in the normal post-menopausal breast and the effects of hormone replacement therapy.
        Br J Cancer. 1998; 78: 945-949
        • Lundstrom E.
        • Christow A.
        • Kersemaekers W.
        • et al.
        Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density.
        Am J Obstet Gynecol. 2002; 186: 717-722
        • Gompel A.
        • Malet C.
        • Spritzer P.
        • Lalardrie J.-P.
        • Kuttenn F.
        • Mauvais-Jarvis P.
        Progestin effect on cell proliferation an 17 b-hydroxysteroid dehydrogenase activity in normal human breast cells in culture.
        J. Clin. Endocrinol. Metab. 1986; 63: 1174-1180
        • Gompel A.
        • Chaouat M.
        • Jacob D.
        • Kloosterboer H.J.
        • Perrot J.Y.
        • Rostene W.
        Tibolone effects in breast cells in vitro studies.
        Fertil. Steril. 2002; 78: 351-359
        • Mc Manus M.J.
        • Welsch C.W.
        The effect of estrogen, progesterone, thyroxine, and human placental lactogen on DNA synthesis of human breast ductal epithelium maintained in athymic nude mice.
        Cancer. 1984; 54: 1920-1927
        • Musgrove E.A.
        • Lee C.S.L.
        • Sutherland R.L.
        Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor, epidermal growth factor, c-fos, and c-myc genes.
        Mol Cell Biol. 1991; 11: 5032-5043
        • Vignon F.
        • Bardon S
        • Chalbos D
        • Rochefort H.
        Antiestrogenic effect of R5020, a synthetic progestin in human breast cancer cells in culture.
        J. Clin. Endocrinol. Metab. 1983; 56: 1124-1130
        • Musgrove E.A.
        • Swarbrick A.
        • Lee C S.L.
        • Cornish A.L.
        • Sutherland R.L.
        Mechanisms of cyclin-dependent kinase inactivation by progestins.
        Mol Cell Biol. 1998; 18: 1812-1825
        • Groshong S.D.
        • Owen G.I.
        • Grimison B.
        • et al.
        Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependant kinase inhibitors, p21 and p27kip1.
        Mol Endocrinol. 1997; 11: 1593-1607
        • Richer J.
        • Lange C.A.
        • Manning N.G.
        • Owen G.
        • Powell R.
        • Horwitz K.B.
        Convergence of progesterone with growth factor and cytokine signaling in breast cancer.
        J. Biol. Chem. 1998; 273: 31317-31326
        • Bassler R.
        Morphology of hormone induced structural changes in the female breast.
        Curr. Top. 1970; 53: 1-89
        • Grubbs J.
        • Farnell D.R.
        • Hill D.L.
        • Mc Donough K.C.
        Chemo-prevention of N-nitro-N-methylurea-induced mammary cancers by pretreatment with 17 β-estradiol and progesterone.
        J. Natl. Cancer Inst. 1985; 74: 927-930
        • Gompel A.
        • Chaouat M.
        • Jacob D.
        • Perrot J.Y.
        • Kloosterboer H.J.
        • Rostene W.
        In vitro studies of tibolone in breast cells.
        Fertil. Steril. 2002; 78: 351-359
        • Kandouz M.
        • Lombet A.
        • Perrot J-Y.
        • et al.
        Proapoptotic effects of antiestrogens, progestines and androgen in breast cancer cells.
        J. Steroid Biochem. Mol. Bio. 1999; 69: 463-471
        • Gompel A.
        • Somaı̈ S.
        • Chaouat M.
        • et al.
        Hormonal regulation of apoptosis in breast cells. Hormonal regulation of apoptosis in breast cells and tissues.
        Steroids. 2000; 65: 593-598
        • Somaı̈ S.
        • Chaouat M.
        • Jacob D.
        • et al.
        Antiestrogens are pro-apoptotic in normal human breast epithelial cells.
        Int. J. Cancer. 2003; 105: 607-612
        • Oltvai Z.N.
        • Milliman C.L.
        • Korsmeyer S.J.
        Bcl-2 heterodimerizes in vivo with a conserved homologue bax that accelerates programmed cell death.
        Cell. 1993; 74: 609-619
        • Slee E.A.
        • Harte M.T.
        • Kluck R.M.
        • et al.
        Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -7, -8, and -10 in a caspase-9 dependent manner.
        J. Cell Biol. 1999; 144: 281-292
        • Kandouz M.
        • Siromachkova M.
        • Jacob D.
        • Marquet C.
        • Therwath A.
        • Gompel A.
        Antagonism between estradiol & progestin on bcl-2 expression in breast cancer cells.
        Int. J. Cancer. 1996; 68: 120-125
        • Teixeira C.
        • Reed J.C.
        • Pratt M.A.C.
        Estrogen promotes chemotherapeutic drug resistance by a mechanism involving bcl-2 proto-oncogene expression in human breast cancer cells.
        Cancer Res. 1995; 55: 3902-3907
        • Filardo E.
        • Quinn J.
        • Raymond Frackelton A.
        • Bland K.
        Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis.
        Mol Endocrinol. 2002; 16: 70-84
        • Ahola T.
        • Alkio N.
        • Manniven T.
        • Ylikomi T.
        Progestin and G protein-coupled receptor 30 inhibit. Mitogen-activated protein kinase activity in MCF-7 breast cancer cells.
        Endocrinology. 2002; 143: 4620-4626
        • Ahola T.
        • Manniven T.
        • Alkio N.
        • Ylikomi T.
        G protein-coupled receptor 30 is critical for a progestin-induced growth inhibition in MCF-7 breast cancer cells.
        Endocrinology. 2002; 143: 3376-3384
        • Simak A.
        • Coombes R.C.
        Endocrine-responsive breast cancer and strategies for combatting resistance.
        Nat Rev/Cancer. 2002; 2: 101-115
        • Mote P.A.
        • Bartow S.
        • Tran N.
        • Clarke C.L.
        Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis.
        Breast Cancer Res. Treat. 2002; 72: 163-172
        • Kristensen V.N.
        • Bressen-Dale A.L.
        Molecular epidemiology of breast cancer: genetic variation in steroid hormone metabolism.
        Mutation Res. 2000; 462: 323-333