title: Effects of Combination of Estradiol with Selective Progesterone Receptor Modulators (SPRMs) on Human Breast Cancer Cells In Vitro and In Vivo.
abstract: Use of estrogen or estrogen/progestin combination was an approved regimen for menopausal hormonal therapy (MHT). However, more recent patient-centered studies revealed an increase in the incidence of breast cancer in women receiving menopausal hormone therapy with estrogen plus progestin rather than estrogen alone. Tissue selective estrogen complex (TSEC) has been proposed to eliminate the progesterone component of MHT with supporting evidences. Based on our previous studies it is evident that SPRMs have a safer profile on endometrium in preventing unopposed estrogenicity. We hypothesized that a combination of estradiol (E2) with selective progesterone receptor modulator (SPRM) to exert a safer profile on endometrium will also reduce mammary gland proliferation and could be used to prevent breast cancer when used in MHT. In order to test our hypothesis, we compared the estradiol alone or in combination with our novel SPRMs, EC312 and EC313. The compounds were effectively controlled E2 mediated cell proliferation and induced apoptosis in T47D breast cancer cells. The observed effects were found comparable that of BZD in vitro. The effects of SPRMs were confirmed by receptor binding studies as well as gene and protein expression studies. Proliferation markers were found downregulated with EC312/313 treatment in vitro and reduced E2 induced mammary gland proliferation, evidenced as reduced ductal branching and terminal end bud growth in vivo. These data supporting our hypothesis that E2+EC312/EC313 blocked the estrogen action may provide basic rationale to further test the clinical efficacy of SPRMs to prevent breast cancer incidence in postmenopausal women undergoing MHT.
authors.affiliation: Evestra, Inc, 14508 Omicron Drive, San Antonio, TX 78245, United States of America.
authors.forename: Hareesh B
authors.initials: HB
authors.lastname: Nair
authors.affiliation: Evestra, Inc, 14508 Omicron Drive, San Antonio, TX 78245, United States of America.
authors.forename: Bindu
authors.initials: B
authors.lastname: Santhamma
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229, United States of America.
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Krishnegowda
authors.affiliation: School of Chemistry, Indian Institute of Science Education and Research, Thiruvananthapuram, 695016, India.
authors.forename: Kalarikkal V
authors.initials: KV
authors.lastname: Dileep
authors.affiliation: Evestra, Inc, 14508 Omicron Drive, San Antonio, TX 78245, United States of America.
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Nickisch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use*; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods; D006801:Humans; D008593:Menopause / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011980:Receptors, Progesterone / Q000378:metabolism*
chemical_list: D004967:Estrogens; D011980:Receptors, Progesterone; D004958:Estradiol