Supplementary Figure 7. Effects of progestin, MPA, and Dex on E2-stimulated growth in MCF-7:WS8 cells. from Molecular Modulation of Estrogen-Induced Apoptosis by Synthetic Progestins in Hormone Replacement Therapy: An Insight into the Women's Health Initiative Study

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posted on 2023-03-30, 22:43 authored by Elizabeth E. Sweeney, Ping Fan, V. Craig Jordan

Supplementary Figure 6. MCF-8:WS8 cells were transferred to estrogen-free medium for 3 days. The, cells were loaded in 24-well plates. A. MCF-7:WS8 cells were treated with vehicle, 0.01µM R5020, 1nM E2, and 0.01µM R5020+1nM E2. Cells were harvested after 7 days treatment and DNA was quantified. P<0.05, * compared with control. P<0.001, ** compared with control. B. MCF-7:WS8 cells were treated with vehicle, different concentrations of MPA as indicated, 1nM E2, and different concentrations of MPA+1nM E2. Cells were harvested after 7 days treatment and DNA was quantified. P<0.05, * compared with E2-treated group. P<0.001, ** compared with control. C. MCF-7:WS8 cells were treated with vehicle, different concentrations of Dex as indicated, 1nM E2, and different concentrations of Dex+1nM E2. Cells were harvested after 7 days treatment and DNA was quantified. P<0.05, * compared with E2-treated group. P<0.001, ** compared with control.

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ARTICLE 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. Cancer Res; 74(23); 7060–8. ©2014 AACR.