A tissue-selective
estrogen complex (TSEC), combining a
selective estrogen receptor modulator,
bazedoxifene (BZA), with
conjugated equine estrogen (CEE), represents a novel strategy of menopausal
hormone therapy without involving a
progestin. We hypothesized that the antiestrogenic properties of BZA can also block the
estrogenic effects of CEE on breast tissue and thereby prevent
breast cancer in women. To test our hypothesis, the effects of
estradiol (E(2)), CEE, and BZA on mammary gland and
breast cancer xenografts were assessed in mouse models. In immature castrate mice, BZA completely blocked CEE- or E(2)-stimulated ductal and terminal end bud growth of mammary gland as well as
estrogen-responsive gene expression. As a positive control, E(2) stimulated
tumor growth in nude mice bearing MCF-7 xenografts. This effect was completely blocked by BZA as were E(2)-stimulated expression of PR, pS2 (
trefoil factor 1), cMyc, and AREG; the enhancement of Ki67 and
proliferating cell nuclear antigen (
PCNA); and the antiapoptotic effect. CEE was much less potent than E(2) in stimulating Ki67, reducing apoptosis, and stimulating gene expression, but all effects were blocked by BZA. Unexpectedly, CEE alone, even at high doses, did not stimulate
tumor growth. As confirmation of its absorption and deconjugation, CEE caused a 6-fold increase in uterine weight and stimulation of gene expression. These data support our hypothesis that the net effect of the CEE/BZA TSEC is to block
estrogen action in benign and malignant breast tissue. These findings provide a rationale for a clinical study to determine whether this TSEC prevents
breast cancer in women.