Pro-Apoptotic Effects of Estetrol on Long-Term Estrogen-Deprived Breast Cancer Cells and at Low Doses on Hormone-Sensitive Cells.

Purpose: Postmenopausal women with estrogen receptor-positive breast cancers often respond initially to tamoxifen or aromatase inhibitor therapy. Resistance to these treatments usually develops within 12 to 18 months. Clinical studies have demonstrated that high-dose estrogen can induce regression of these endocrine-resistant tumors. However, side-effects of high-dose estradiol (E) or diethylstilbestrol (DES) limit their usage. Estetrol (E) is the most abundant estrogen during pregnancy and has a long half-life and a low potential for side-effects. Estetrol might then provide benefits similar to DES on tumor regression but with lesser toxicity.

Methods: In this study, we systematically evaluated the effects of E on cell proliferation and apoptosis in wild-type MCF-7 and long-term estrogen-deprived (LTED) MCF-7 cells and compared its effects with E and estriol (E).

Results: Estetrol induced apoptosis in LTED cells but stimulated growth of MCF-7 cells at concentrations from 10 to 10 M. These effects of E are similar to those of E but require much higher doses. Differing from E, E at 10 M induced apoptosis in MCF-7 cells and another pregnancy estrogen, E, acted similarly. No antagonistic effect of E or E against E occurred when they were combined.

Conclusions: The pro-apoptotic effects of E and E on LTED cells and at low doses on MCF-7 cells indicate that these steroids could be used as therapeutic agents for endocrine-resistant or sensitive breast cancer.