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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: (<jats:italic>i<\/jats:italic>) whether CEE exert effects on breast cancer which differ from those of estradiol (E<jats:sub>2<\/jats:sub>) and (<jats:italic>ii<\/jats:italic>) whether BZA antagonize the effects of E<jats:sub>2<\/jats:sub> and CEE on breast cancer? Two rodent models (NMU and ACI) were used to compare the effect of CEE with E<jats:sub>2<\/jats:sub> on mammary tumor formation, proliferation and apoptosis. In both the NMU and ACI models, E<jats:sub>2<\/jats:sub> significantly increased tumor incidence and multiplicity whereas in striking contrast CEE did not, even though the estrogenic effects of CEE and E<jats:sub>2<\/jats:sub> on uterine weight were identical. Mechanistically E<jats:sub>2<\/jats:sub> blocked whereas CEE stimulated apoptosis (cleaved caspase\u20103) in ACI animals and only E<jats:sub>2<\/jats:sub> stimulated proliferation (Ki67). BZA exerted highly potent anti\u2010estrogenic effects on tumors by completely blocking palpable tumor formation. These data suggest that the CEE\/BZA TSEC may be a safer, breast\u2010antagonistic, MHT agent for women and might have potential to prevent breast cancer while relieving menopausal symptoms.<\/jats:p>","DOI":"10.1002\/ijc.31401","type":"journal-article","created":{"date-parts":[[2018,3,26]],"date-time":"2018-03-26T01:34:48Z","timestamp":1522028088000},"page":"1259-1268","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Effect of a tissue selective estrogen complex on breast cancer: Role of unique properties of conjugated equine estrogen"],"prefix":"10.1002","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7313-8516","authenticated-orcid":false,"given":"Wei","family":"Yue","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine University of Virginia Health Systems Charlottesville 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