SERMs Attenuate Estrogen-Induced Malignant Transformation of Human Mammary Epithelial Cells by Upregulating Detoxification of Oxidative Metabolites

Abstract

The risk of developing hormone-dependent cancers with long-term exposure to estrogens is attributed both to proliferative, hormonal actions at the estrogen receptor (ER), and chemical carcinogenesis elicited by genotoxic, oxidative estrogen metabolites. Non-tumorigenic MCF-10A human breast epithelial cells are classified as ER(−) and undergo estrogen-induced malignant transformation. Selective estrogen receptor modulators (SERMs), in use for breast cancer chemoprevention and for post-menopausal osteoporosis, were observed to inhibit malignant transformation, as measured by anchorage-independent colony growth. This chemopreventive activity was observed to correlate with reduced levels of oxidative estrogen metabolites, cellular ROS, and DNA oxidation. The ability of raloxifene, desmethylarzoxifene (DMA), and bazedoxifene to inhibit this chemical carcinogenesis pathway was not shared by 4-hydroxytamoxifen. Regulation of Phase 2 rather than Phase 1 metabolic enzymes was implicated mechanistically: raloxifene and DMA were observed to upregulate sulfotransferase (SULT 1E1) and glucuronidase (UGT 1A1). The results support upregulation of Phase 2 metabolism in detoxification of catechol estrogen metabolites leading to attenuated ROS formation as a mechanism for inhibition of malignant transformation by a subset of clinically important SERMs.

Carvedilol suppresses malignant proliferation of mammary epithelial cells through inhibition of the ROS‑mediated PI3K/AKT signaling pathway

“…Tamoxifen and raloxifene are the classical chemopreventive drugs used to prevent estrogen receptor (ER)-positive breast cancer that have minimal effects on ER-negative breast cancer (34). The results of the present study indicate that CAR may be considered a novel chemopreventive agent, notably in the prevention of ER-negative breast cancer, since MCF-10A cells rarely express ER (35). The antioxidant effect of CAR may contribute to its cancer-preventive activity.…”

Role of dietary bioactive natural products in estrogen receptor-positive breast cancer

“…The receptor-mediated cell divisions could increase cell proliferation and accumulation of DNA damage with mutational events [30]. In the ER independent pathway, carcinogenic effects of estrogens are believed to occur through the actions of estrogen metabolites [2, 5, 31]. Estrogen metabolism regulated by phase I CYP enzymes mediates the hydroxylation of estradiols and estrones [2, 32].…”

Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer

“…27-29 We have focused upon a deeper understanding of ER ligands based upon the benzothiophene scaffold, common to raloxifene and arzoxifene. 30-41 Recently, we demonstrated in two different animal models of tamoxifen-resistant breast cancer, that a prototype benzothiophene ShERPA caused regression of established xenografts, in the absence of the uterine weight gain shown by E 2 . 42 Herein we report the design, synthesis, optimization, and characterization of potent ShERPAs with potential for treatment of endocrine-independent and tamoxifen-resistant breast cancer.…”

“…The SERM, raloxifene, in clinical use for postmenopausal osteoporosis for over a decade, appears safe and noncarcinogenic and is clinically indicated for chemoprevention of invasive breast cancer. Arzoxifene, an analogue of raloxifene and a “third generation” SERM, demonstrated a favorable profile in preclinical studies, and its active metabolite is more potent than raloxifene. − The indole SERM, bazedoxifene, was recently approved in Europe for postmenopausal osteoporosis. − We have focused upon a deeper understanding of ER ligands based upon the benzothiophene scaffold, common to raloxifene and arzoxifene. − Recently, we demonstrated in two different animal models of tamoxifen-resistant breast cancer that a prototype benzothiophene ShERPA caused regression of established xenografts in the absence of the uterine weight gain shown by E 2 . Herein we report the design, synthesis, optimization, and characterization of potent ShERPAs with potential for treatment of endocrine-independent and tamoxifen-resistant breast cancer.…”