Supplementary Figure 6. A. MCF-7:WS8 cells were transfected with an ERE-luciferase reporter construct for 24 hours, then treated with vehicle, 1µM ICI, 1µM R5020, 1µM RU486, 1nM E2, 1µM MPA, 1µM NETA, or combinations for 24 hours. ERE activity was measured by luciferase assay and normalized to vehicle control. Means represent samples in triplicate. B. MCF-7:WS8 cells were transfected with an ERE-luciferase reporter construct for 24 hours, then treated with vehicle, 1µM 4-OHT, 1µM R5020, 1µM RU486, 1nM E2, 1µM MPA, 1µM NETA, or combinations for 24 hours. ERE activity was measured by luciferase assay and normalized to vehicle control. Means represent samples in triplicate. Error bars too small to visualize.
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.
