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 comprise 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 post-menopausal women, while 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 post-menopausal breast cancer cell environment. MPA is able to modify E2-induced apoptosis in MCF-7:5C cells. MPA, similar to dexamethasone (Dex) increases GR transcriptional activity, increases SGK1, a GR target gene, and can be blocked by RU486 (an antiglucocorticoid), suggesting it functions through the GR. Norethindrone acetate (NETA), another progestin used in HRT, acts like an estrogen at high doses, up-regulating ER-target genes and generating apoptosis in MCF-7:5C cells. The data suggests that women taking HRT comprising an estrogen plus MPA may have an increased the 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.

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

“…Indeed a high dose of MPA used as a breast cancer therapy or as a depot injection for contraception, causes weight gain as a glucocorticoid type side effect. The glucocorticoid and progestin activating of synthetic progestins is recognised in the laboratory and recent study (181) addressed the hypothesis that the glucocorticoid properties of MPA could influence and modulate the apoptotic actions of estradiol in LTED breast cancer cells.…”

“…However these clues that MPA might modulate estrogen-induced apoptosis over time and create new cell populations that grow into tumours, is an important finding: MPA could select for surviving breast cancers by modulating estrogen-induced apoptosis over years of therapy in women who are a decade or more from menopause as documented in the WHI (138). Laboratory evidence for modifying apoptosis by estrogen through the glucocorticoid action of MPA was presented by Sweeney et al (181). This new finding coupled with the knowledge that rapid plasticity of hormone resistance occurs as a response to selection pressure (172, 175–177), suggest a fundamental principle has now emerged based on selection pressure over years in patients..…”

Integration of Downstream Signals of Insulin-like Growth Factor-1 Receptor by Endoplasmic Reticulum Stress for Estrogen-Induced Growth or Apoptosis in Breast Cancer Cells

“…Laboratory findings that re-transplantation of tamoxifen-stimulated tumors into successive generations of athymic mice over 5 years results in the selection of a resistant tumor cell population that is killed by physiological levels of E 2 (2, 3), has resulted in the new biology of E 2 -induced apoptosis (4–7). Indeed, E 2 -induced apoptosis has been used successfully to treat breast cancer after the failure of AI therapy (8) and to explain the action of E 2 replacement therapy for postmenopausal women in their 60s having a lower incidence of breast cancer and mortality (9, 10). The laboratory and clinical data describing the effects of estrogens to cause tumor cell death and tumor regression have been linked to E 2 -induced apoptosis in vulnerable cell populations created by selection pressure in long term E 2 -deprived environments (11).…”

The Effect of Menopausal Hormone Therapies on Breast Cancer

“…Sweeney et al identified a potential role for GR in breast cancer pathogenesis by studying MPAs effect on breast cancer cells as compared to that of dexamethasone (Dex) and norethindrone acetate (NETA). 19 Like Dex, MPA blocked E2-induced apoptosis, allowing for continued proliferation of these cells. In addition, like Dex, MPA blocked E2-induced genes related to apoptosis.…”

“…Sweeney et al found that MPA combined with E2 stimulated proliferation in long-term estrogen deprived MCF-7 (MCF-7:5C) cells, while E2 alone resulted in cell death. 19 …”