Abstract
Tamoxifen is administered for estrogen receptor positive (ER+) breast cancers, but it can induce uterine endometrial cancer and non-alcoholic fatty liver disease (NAFLD). Importantly, ten years of tamoxifen treatment has greater protective effect against ER+ breast cancer than five years of such treatment. Tamoxifen was also approved by the FDA as a chemopreventive agent for those deemed at high risk for the development of breast cancer. The side effects are of substantial concern because of these extended methods of tamoxifen administration. In this study, we found that anordrin, marketed as an antifertility medicine in China, inhibited tamoxifen-induced endometrial epithelial cell mitosis and NAFLD in mouse uterus and liver as an anti-estrogenic and estrogenic agent, respectively. Additionally, compared with tamoxifen, anordiol, the active metabolite of anordrin, weakly bound to the ligand binding domain of ER-α. Anordrin did not regulate the classic estrogen nuclear pathway; thus, it did not affect the anti-tumor activity of tamoxifen in nude mice. Taken together, these data suggested that anordrin could eliminate the side effects of tamoxifen without affecting its anti-tumor activity.
Highlights
Tamoxifen was the first FDA-approved drug for breast cancer patients with positively expressed estrogen receptors (ER)[1]
Because tamoxifen induces the mitosis of endometrial epithelial cells (EEC), as an estrogenic agent[4,5,6,11], it is considered the mechanism of tamoxifen-induced uterine endometrial cancer
Hematoxylin and eosin (H&E) staining of paraffin-embedded uterine sections revealed that 3 mg anordrin (ANO) per kilogram food (3 mg/kg), and 45 mg tamoxifen (TAM) per kilogram food (45 mg/kg) increased the thickness of the EEC (Fig. 1a and b, TAM, ANO); mitotic EEC did not occur in the anordrin (ANO) group (Fig. 1a, ANO)
Summary
Tamoxifen was the first FDA-approved drug for breast cancer patients with positively expressed estrogen receptors (ER)[1]. Tamoxifen was the first FDA-approved chemopreventive agent for those deemed at high risk for the development of breast cancer[3]. Previous studies into the molecular mechanism of tamoxifen-induced side effects resulted in the discovery of the classic estrogen nuclear pathway and membrane-initiated estrogen signal (MIES) pathways, which are modulated by membrane-bound estrogen receptors, orphan G-protein coupled estrogen receptor 30 (GPER1) and ER-α–364–6. To eliminate tamoxifen-induced side effects and understand the physiological functions of GPER1 and ER-α-36, we screened selective estrogen receptor modulators, which, compared with tamoxifen, clinically exerted the opposite estrogenic activity in MIES. We found that anordrin and tamoxifen exerted opposing estrogenic effects to modulate the physiological function of MIES in a mouse uterus and liver. Combined administration of tamoxifen with anordrin can eliminate the side effects of tamoxifen without affecting its anti-tumor activity in nude mice
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
