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

Xueyan Zhou1, Yun Zhao1, Juan Wang1

  • 1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.

Insights

Resveratrol prevents breast cancer by restoring estrogen balance. It upregulates NRF2-UGT1A8 signaling, enhancing catechol estrogen metabolism and reducing DNA damage.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Estrogen is crucial in breast cancer development.
  • Resveratrol exhibits chemo-preventive properties, but its mechanism is unclear.
  • Estrogen homeostasis is disrupted in breast cancer, leading to carcinogenic catechol estrogen accumulation.

Purpose of the Study:

  • To elucidate the mechanism behind resveratrol's antitumor activity in breast cancer.
  • To investigate the role of the NRF2-UGT1A8 signaling pathway in estrogen metabolism and breast cancer.
  • To establish resveratrol's potential in regulating estrogen homeostasis via this pathway.

Main Methods:

  • Studied estrogen homeostasis in breast cancer patients and rat models.
  • Investigated the expression of UDP-glucuronosyltransferase 1A8 (UGT1A8) and nuclear factor erythroid 2-related factor 2 (NRF2).
  • Utilized resveratrol treatment, luciferase reporter assays, and small-interfering RNA (siRNA) for NRF2 silencing.

Main Results:

  • Breast cancer rat models showed down-regulated mammary NRF2-UGT1A8 signaling.
  • Resveratrol treatment upregulated NRF2 and UGT1A8, accelerating catechol estrogen metabolism.
  • Resveratrol inhibited estrogen-induced DNA damage and suppressed breast cancer development.
  • Luciferase assays confirmed resveratrol activates UGT1A8 via NRF2 transcriptional activity.
  • NRF2 silencing abolished resveratrol's preventive effects, highlighting the NRF2-UGT1A8-estrogen metabolism axis.

Conclusions:

  • Resveratrol's antitumor effects in breast cancer are mediated by the NRF2-UGT1A8-estrogen metabolism axis.
  • Resveratrol regulates estrogen homeostasis through the NRF2-UGT1A8 signaling pathway.
  • This study reveals a novel link between estrogen glucuronidation metabolism and breast cancer pathology.

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