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  • Molecular modulation of estrogen-induced apoptosis by synthetic progestins in hormone replacement therapy: an insight into the women's health initiative study.

Molecular modulation of estrogen-induced apoptosis by synthetic progestins in hormone replacement therapy: an insight into the women's health initiative study.

Cancer research (2014-10-12)
Elizabeth E Sweeney, Ping Fan, V Craig Jordan
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.

MATERIALS
Product Number
Brand
Product Description

Norethisterone, European Pharmacopoeia (EP) Reference Standard
Medroxyprogesterone acetate, European Pharmacopoeia (EP) Reference Standard
Supelco
Dexamethasone solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Supelco
Progesterone, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Medroxyprogesterone 17-acetate, ≥97% (HPLC)
Sigma-Aldrich
Progesterone, γ-irradiated, BioXtra, suitable for cell culture
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-15, ascites fluid
Sigma-Aldrich
19-Norethindrone, ≥98%, powder
Sigma-Aldrich
Progesterone, ≥99%
Supelco
Medroxyprogesterone 17-acetate, VETRANAL®, analytical standard
Supelco
Progesterone, VETRANAL®, analytical standard
Sigma-Aldrich
Propylene glycol monomethyl ether acetate, ReagentPlus®, ≥99.5%
Sigma-Aldrich
Progesterone, meets USP testing specifications
Progesterone, European Pharmacopoeia (EP) Reference Standard
USP
Norethindrone, United States Pharmacopeia (USP) Reference Standard
Progesterone for peak identification, European Pharmacopoeia (EP) Reference Standard
Progesterone for system suitability, European Pharmacopoeia (EP) Reference Standard
Dexamethasone for peak identification, European Pharmacopoeia (EP) Reference Standard
USP
Medroxyprogesterone acetate, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Progesterone, powder, BioReagent, suitable for cell culture
USP
Progesterone, United States Pharmacopeia (USP) Reference Standard
Supelco
4-Hydroxytamoxifen, analytical standard, (E) and (Z) isomers (50:50)
Medroxyprogesterone acetate for system suitability, European Pharmacopoeia (EP) Reference Standard
Supelco
Dexamethasone, VETRANAL®, analytical standard
Sigma-Aldrich
Dexamethasone, tested according to Ph. Eur.
Sigma-Aldrich
Dexamethasone, powder, γ-irradiated, BioXtra, suitable for cell culture, ≥80% (HPLC)
Sigma-Aldrich
4-Hydroxytamoxifen, ≥70% Z isomer (remainder primarily E-isomer)
Sigma-Aldrich
Dexamethasone, meets USP testing specifications
Sigma-Aldrich
Dexamethasone, ≥98% (HPLC), powder
Sigma-Aldrich
Mifepristone, ≥98%