title: Molecular modulation of estrogen-induced apoptosis by synthetic progestins in hormone replacement therapy: an insight into the women's health initiative study.
abstract: Hormone replacement therapy (HRT) is widely used to manage menopausal symptoms in women and can be comprised of an estrogen alone or an estrogen combined with a progestin. The Women's Health Initiative demonstrated in their randomized trials that estrogen alone HRT decreases the risk of breast cancer in postmenopausal women, whereas combined estrogen plus a progestin (medroxyprogesterone acetate, MPA) HRT increases this risk. Long-term estrogen-deprived MCF-7:5C cells were used to model the postmenopausal breast cancer cell environment. MPA is able to modify E2-induced apoptosis in MCF-7:5C cells. MPA, similar to dexamethasone, increases glucocorticoid receptor (GR) transcriptional activity, increases SGK1, a GR target gene, and can be blocked by RU486 (an antiglucocorticoid), suggesting that it functions through the GR. Norethindrone acetate (NETA), another progestin used in HRT, acts like an estrogen at high doses, upregulating estrogen receptor target genes and generating apoptosis in MCF-7:5C cells. The data suggest that women taking HRT comprising an estrogen plus MPA may have an increased risk of breast cancer due to MPA acting as a glucocorticoid and blunting E2-induced apoptosis in this environment. Therefore, perhaps other approved progestins (e.g., NETA) should be considered as alternatives to MPA.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Sweeney
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia.
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia. vcj2@georgetown.edu.
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism; D020249:Hormone Replacement Therapy / Q000009:adverse effects*; D006801:Humans; D061986:MCF-7 Cells; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009640:Norethindrone / Q000031:analogs & derivatives / Q000494:pharmacology; D000077563:Norethindrone Acetate; D017698:Postmenopause / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D045167:Progesterone Congeners / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D012306:Risk; D016387:Women's Health
chemical_list: D004967:Estrogens; D005938:Glucocorticoids; D045167:Progesterone Congeners; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D000077563:Norethindrone Acetate; D017258:Medroxyprogesterone Acetate; D009640:Norethindrone