Resveratrol represses estrogen-induced mammary carcinogenesis through NRF2-UGT1A8-estrogen metabolic axis activation.

Estrogen plays a pivotal role in the pathological development of breast cancer. Resveratrol has chemo-preventive effects against breast cancer, whereas, the mechanism of antitumor activities of resveratrol remains unanswered. In this study, we showed that estrogen homeostasis profile was disturbed in both breast cancer patients and in experimental breast cancer model rats, with carcinogenic catechol estrogens significantly accumulated in the mammary tissues. UDP-glucuronosyltransferase 1A8 (UGT1A8) is an important phase II drug-metabolizing enzymes which involved in the metabolism of catechol estrogens. Here we found that the mammary nuclear factor erythroid 2-related factor 2 (NRF2) - UGT1A8 signaling was down-regulated in breast cancer rats, whereas treatment with resveratrol could upregulate the expression of NRF2 and UGT1A8, accelerate metabolic elimination of catechol estrogens, inhibit estrogen-induced DNA damage and suppress the pathological development of breast cancer. In addition, luciferase reporter assay suggested that resveratrol activated the expression of UGT1A8 by up-regulating the transcriptional activity of NRF2. Small-interfering RNA-mediated silencing of NRF2 abolished resveratrol-mediated preventive effects indicated that the antitumor effect of resveratrol is based on NRF2-UGT1A8-estrogen metabolism axis. Taken together, we established the resveratrol regulating potential on estrogen homeostasis based on NRF2-UGT1A8 signaling pathway, and also provided a novel link between estrogen glucuronidation metabolism and breast cancer pathological development.