Abstract 3322: Estrogen and nuclear respiratory factor 1 act as joint mediators of redox modulation and stem cell aging that contribute in the pathogenesis of breast cancer

Abstract

Abstract Deterioration of adult stem cell function with increasing age is a risk factor of breast cancer. Metastasis of breast cancer seems to be also influenced by aging or senescent cells overexpressing mitophagy/autophagy genes. Recently, estrogen, ROS, mitochondria and NRF1 activity have been implicated with stem cell aging, health and longevity. The exact underlying mechanisms of how aging of stem cells may increase the susceptibility to estrogen-induced carcinogenicity remain unknown. The main objective of this study was to examine whether estrogen, through activation of NRF1-mediated redox modulation and autophagic genes involved in senescence of stem cells, contributes in the development of breast cancer. To test this hypothesis, first we investigated the role of NRF1 to induce stemness by re-programming of breast epithelial cells (MCF-10A) and breast cancer cells (MCF-7 and MDA-MB231). We found that NRF1 promoted pluripotency markers: Oct4, Sox 2, and Nanog compare to MCF10A, MCF-7 or MDAMB 231 control cells. Loss of E-cadherin expression and gain of N-cadherin and vimentin expression in NRF1 overexpressing cells suggested that NRF1 promotes epithelial- mesenchymal transition. NRF1 promoted the ability to differentiate in vitro into a variety of cells (e.g chondrocytes, neurons, and smooth muscle cells). This suggested that NRF1 promotes multilineage differentiation potentials. Our data also showed that higher expression of NRF1 increased sizes of spheroids and ROS levels compared to controls. Mitophagy/Autophagy that regulates clearance of damaged mitochondria/apoptotic cells has important functions in regulating stem cell aging and tumorigenesis. Therefore, we examined the effect of estrogen on aging-associated diseases-related genes in NRF1 overexpressing as well as NRF1 silenced cells. Autophagy/Mitophagy/Apoptosis-related genes - BNIP3, PINK1, DJ-1 and LKB1 were altered in response to exposure of a carcinogenic concentration of estrogen. This effect of estrogen on these genes was further amplified by NRF1 overexpression and was inhibited by loss of NRF1. In summary, estrogen and NRF1 act as joint mediators of stem cell fate and reprogramming through a panel of critical stem cell proteins involved in modulating senescence and cell death. NRF1 seems to function as a rheostat to coordinate various cellular processes, such as resistance to apoptosis, autophagy and mitophagy of stem cells required for the stem cell aging as well as for the pathogenesis of breast cancer. Citation Format: Juan Vazquez, Deodutta Roy, Jayant Das. Estrogen and nuclear respiratory factor 1 act as joint mediators of redox modulation and stem cell aging that contribute in the pathogenesis of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3322.