SERMs Attenuate Estrogen-Induced Malignant Transformation of Human Mammary Epithelial Cells by Upregulating Detoxification of Oxidative Metabolites
| Autor: | Rui Xiong, Marton I. Siklos, Jaewoo Choi, Bradley T. Michalsen, Robert A. Scism, R. Esala P. Chandrasena, Emily N. Thayer, Sujeewa C. Piyankarage, Yijin Wang, Shuai Wang, L. P. Madhubhani P. Hemachandra, Judy L. Bolton, Hitisha K. Patel, Gregory R. J. Thatcher |
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| Rok vydání: | 2014 |
| Předmět: |
Selective Estrogen Receptor Modulators
Cancer Research Indoles medicine.drug_class Estrogen receptor Thiophenes Pharmacology Biology medicine.disease_cause Article Malignant transformation Piperidines medicine Humans Raloxifene Mammary Glands Human Cells Cultured Estradiol Raloxifene Hydrochloride Oxidants Up-Regulation Oxidative Stress Tamoxifen Cell Transformation Neoplastic Oncology Cytoprotection Selective estrogen receptor modulator Estrogen Inactivation Metabolic MCF-7 Cells Reactive Oxygen Species Carcinogenesis hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | Cancer Prevention Research. 7:505-515 |
| ISSN: | 1940-6215 1940-6207 |
| Popis: | 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 to chemical carcinogenesis elicited by genotoxic, oxidative estrogen metabolites. Nontumorigenic MCF-10A human breast epithelial cells are classified as ER− and undergo estrogen-induced malignant transformation. Selective estrogen receptor modulators (SERM), in use for breast cancer chemoprevention and for postmenopausal 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 reactive oxygen species (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 II rather than phase I 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 II 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. Cancer Prev Res; 7(5); 505–15. ©2014 AACR. |
| Databáze: | OpenAIRE |
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