Abstract
Use of estrogen or estrogen / progestin combination was an approved regimen for menopausal hormonal therapy (MHT). However, more recent patient-centered studies revealed an increase in the incidence of breast cancer in women receiving menopausal hormone therapy with estrogen plus progestin rather than estrogen alone. Tissue selective estrogen complex (TSEC) has been proposed to eliminate the progesterone component of MHT with supporting evidences. Based on our previous studies it is evident that SPRMs have a safer profile on endometrium in preventing unopposed estrogenicity. We hypothesized that a combination of estradiol (E2) with selective progesterone receptor modulator (SPRM) to exert a safer profile on endometrium will also reduce mammary gland proliferation and could be used to prevent breast cancer when used in MHT. In order to test our hypothesis, we compared the estradiol alone or in combination with our novel SPRMs, EC312 and EC313. The compounds were effectively controlled E2 mediated cell proliferation and induced apoptosis in T47D breast cancer cells. The observed effects were found comparable that of BZD in vitro. The effects of SPRMs were confirmed by receptor binding studies as well as gene and protein expression studies. Proliferation markers were found downregulated with EC312/313 treatment in vitro and reduced E2 induced mammary gland proliferation, evidenced as reduced ductal branching and terminal end bud growth in vivo. These data supporting our hypothesis that E2+EC312/EC313 blocked the estrogen action may provide basic rationale to further test the clinical efficacy of SPRMs to prevent breast cancer incidence in postmenopausal women undergoing MHT.
Highlights
As per the scientific statement of the Endocrine Society based on the data from the various Women’s Health Initiative studies, the primary areas of benefit of menopausal hormonal therapy (MHT) included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes and, on the other hand, risks included venothrombotic episodes, stroke, and cholecystitis (1)
Since antiprogestins and antiestrogens demonstrated to have deferential effects on cultured breast cancer cells in the presence and absence of estrogenic compounds in the serum and in the medium such as phenol red [29], we have evaluated whether our compounds elicit estrogen agonistic/antagonistic actions in the presence and absence of endogenous estrogen
We have analyzed the presence of endogenous estrogens (RPMI with phenol red and 5% fetal bovine serum (FBS)) and found that each concentration of EC312 and EC313 reduced cell number by approximately 60% with the maximum effect observed at 10nM
Summary
As per the scientific statement of the Endocrine Society based on the data from the various Women’s Health Initiative studies, the primary areas of benefit of MHT included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes and, on the other hand, risks included venothrombotic episodes, stroke, and cholecystitis (1). In a WHI study, a subgroup of women starting MHT between ages 50 and 59 or less than 10 years after onset of menopause, an additional benefit of reduction of overall mortality and coronary artery disease is included. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Emerging scientific evidences suggests that PR action is context-dependent such as hormone exposure (presence versus absence of estrogen) [5, 6], organ site (proliferative in breast versus antiproliferative in uterus) [7], Ligand dependent (growth factor or kinase dependent) [8] and cross reactivity to other nuclear receptors (Onapristone- liver toxicity) [9, 10]
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