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ARSENIC EXPOSURE PROMOTES AGGRESSIVE BREAST CANCER PHENOTYPE

Environmental arsenic (AS) is a class I human carcinogen with established roles in promoting skin, colon, bladder and kidney cancers. The role of AS as a breast carcinogen is less established although numerous studies have indicated that that in cell culture AS promotes the specification of breast cancer towards phenotypes that are estrogen receptor negative (ERα(−)) which are more lethal as well as more challenging to treat. The molecular mechanism involved remain unknown. Our laboratory found that AS promotes alterations in the metabolism of mitochondria reactive oxygen species (ROS) via inhibiting the tumor suppressor Sirtuin 3 which leads to the accumulation of manganese superoxide dismutase (MnSOD) in an acetylated form (MnSOD‐K68Ac) which activates hypoxia induced factor 2α (HIF2α). The activation of HIF2α is a well‐stablished mechanism os stem cell reprogramming that has also been implicated in metastatic recurrence as well as treatment failure in women with breast cancer. Hence, we propose that chrnic AS exposure is a risk factor for the development of ER(−) breast cancer via a mechanism that involves MnSOD acetylation and mitochondria ROS. In support of this idea, we found that exposure of MCF‐7 (normally ERα+), leads to the accumulation of MnSOD‐K68Ac and ER(−) phenotype. Our results indicate that exposure to AS may be a risk factor for the development of ER(−) tumors which are more aggressive and prone to metastasize.