Abstract 240: Natural antioxidants exhibit chemopreventive characteristics through the regulation of CNC-bZip transcription factors in estrogen-induced breast carcinogenesis

Abstract

Abstract Epidemiological data and studies in rodent models strongly support the role of estrogens in the development of breast cancers. Exact mechanisms underlying the initiation and progression of estrogen-related cancers are not clear. Literature evidence and our studies strongly support the role of estrogen metabolism mediated oxidative stress in estrogen-induced breast carcinogenesis. We have recently demonstrated that antioxidants vitamin C (VC) or butylated hydroxyanisole (BHA) severely inhibit 17β-estradiol (E2)-induced breast tumor development in female ACI rats. The objective of this study was to characterize the role of CNC b-zip transcription factors in antioxidant-mediated prevention of breast cancer. Human non-neoplastic breast epithelial cell line MCF-10A was treated with E2, VC, VC + E2, Resveratrol (Res) and Res + E2 for up to 72 hrs. mRNA and protein expression levels of phase-II detoxifying enzymes SOD1, SOD2, SOD3, GPx, NQO1 and transcription factors from CNC b-zip family: Nrf1, Nrf2 and Nrf3 were quantified after treatment with E2 and compared with that of cells treated with antioxidants either alone or in combination with E2. The mRNA as well as protein expression levels of SOD3 and NQO1 were suppressed in MCF-10A cells treated with E2. There was no change in mRNA and protein expression levels of SOD1, SOD2 and GPX in MCF-10A cells treated with E2. Nrf2 mRNA and protein expression levels were also significantly suppressed in E2-treated MCF-10A cells. Vitamin C or Res treatment prevented E2-mediated decrease in SOD3, NQO1 and Nrf2 mRNA and protein expression levels. A significant increase in Nrf1 mRNA and protein expression levels in MCF-10A cells treated with E2 was noted. Further, treatment with antioxidants Res or VC also increased mRNA and protein expression levels of Nrf1. Nrf3 mRNA and protein expression levels were significantly increased in MCF-10A cells treated with E2. This induction was overcome by co-treatment with E2 and VC or Res. Our studies demonstrate that antioxidant-mediated protection against estrogen-induced breast cancer could be through up regulation of phase-II detoxifying enzymes via an Nrf-dependent pathway involving a complex interplay among Nrfs 1, 2 and 3. Note: This abstract was not presented at the meeting. Citation Format: Anwesha Chatterjee, Amruta Ronghe, Fatma Abdalla, Hari K. Bhat. Natural antioxidants exhibit chemopreventive characteristics through the regulation of CNC-bZip transcription factors in estrogen-induced breast carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 240. doi:10.1158/1538-7445.AM2014-240