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(2)) or diethylstilbestrol (DES) limit their usage. Estetrol (E(4)) 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(4) 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(2) and estriol (E(3)). RESULTS: Estetrol induced apoptosis in LTED cells but stimulated growth of MCF-7 cells at concentrations from 10(−11) to 10(−8) M. These effects of E(4) are similar to those of E(2) but require much higher doses. Differing from E(2), E(4) at 10(−12) M induced apoptosis in MCF-7 cells and another pregnancy estrogen, E(3), acted similarly. No antagonistic effect of E(4) or E(3) against E(2) occurred when they were combined. CONCLUSIONS: The pro-apoptotic effects of E(4) and E(3) 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.