Aggressive
estrogen receptor (ER) positive
breast cancer is frequently
tamoxifen-resistant; alternative endocrine approaches exist for
therapy, but not for prevention, particularly in premenopausal women. We examined the efficacy of the selective ER modulator (
Z-endoxifen) as monotherapy and in combination with the selective
progesterone receptor modulators (
onapristone and
ulipristal acetate) in the
tamoxifen-insensitive C3(1)/SV40TAg mouse mammary
tumorigenesis model. Unlike
tamoxifen at human equivalent dose (HED) 101 mg/day,
endoxifen at HED 24 mg/day significantly increased latency and reduced
tumor growth relative to untreated controls.
Ulipristal acetate (UPA) at HED 81 mg/day also significantly increased latency however failed to inhibit
tumor growth, while
onapristone (HED 98 mg/day) had no
tumor prevention efficacy in this model. Addition of UPA to
endoxifen did not enhance preventive efficacy over
endoxifen alone. The expression of genes associated with cell cycle, cell proliferation and extracellular matrix remodeling was similarly repressed by
endoxifen and UPA however only
endoxifen significantly downregulated prominent genes associated with poor prognosis (Col11a1, Il17b, Pdgfa, Tnfrsf11a). Our results indicate that
endoxifen can prevent breast
cancers, even when
tamoxifen-resistant, through its role in favorable tissue remodeling and
immunomodulation.