Effect Of A Tissue Selective Estrogen Complex On Breast Cancer: Role Of Unique Properties Of Conjugated Equine Estrogen

The Women's Health Initiative studies reported that the menopausal hormone therapy (MHT) regimen containing conjugated equine estrogen (CEE) and medroxyprogesterone acetate increased, whereas CEE alone reduced breast cancer incidence. These observations suggest the possibility that CEE might exert unique actions on breast and also suggest the need to eliminate the progestogen from MHT regimens. A MHT regimen called a tissue selective estrogen complex (TSEC), containing CEE plus bazedoxifene (BZA), to avoid the need for a progestogen, was developed and FDA approved. Our study addressed two questions regarding this TSEC: (i) whether CEE exert effects on breast cancer which differ from those of estradiol (E-2) and (ii) whether BZA antagonize the effects of E-2 and CEE on breast cancer? Two rodent models (NMU and ACI) were used to compare the effect of CEE with E-2 on mammary tumor formation, proliferation and apoptosis. In both the NMU and ACI models, E-2 significantly increased tumor incidence and multiplicity whereas in striking contrast CEE did not, even though the estrogenic effects of CEE and E-2 on uterine weight were identical. Mechanistically E-2 blocked whereas CEE stimulated apoptosis (cleaved caspase-3) in ACI animals and only E-2 stimulated proliferation (Ki67). BZA exerted highly potent anti-estrogenic effects on tumors by completely blocking palpable tumor formation. These data suggest that the CEE/BZA TSEC may be a safer, breast-antagonistic, MHT agent for women and might have potential to prevent breast cancer while relieving menopausal symptoms.What's new? To alleviate menopausal discomforts, doctors frequently prescribe hormone therapy that includes conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA). But this combo ups the risk of breast cancer. Here, the authors investigated the safety of CEE paired with bazedoxifene (BZA), a selective estrogen receptor modulator, in rat models. First, they compared CEE and estradiol. While estradiol blocked apoptosis and increased tumor incidence, CEE stimulated apoptosis and showed no effect on tumor incidence or proliferation. They then showed that BZA blocked tumor development in rats treated with estradiol. Long-term clinical trials will show whether these findings hold in humans as well.