Environmental Arsenic Exposures and Breast Cancer Subtype Specification

University Of Illinois At Chicago, Chicago IL

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Abstract

Environmental arsenic (As) is a class I human carcinogen with established roles in promoting skin, bladder, lung and kidney cancers. The role of arsenic as a breast carcinogen is less established although numerous studies have indicated that in cell cultures As promotes the specification of breast cancer cells towards phenotypes that are estrogen receptor negative as well as more lethal and challenging to treat. The molecular mechanisms involved remain unknown. Our laboratory found that As promotes alterations in the metabolism of mitochondrial reactive oxygen species (ROS) via inhibiting the tumor suppressor Sirtuin 3 which leads to the accumulation of manganese superoxide dismutase (MnSOD) in an acetylated/inactive form (MnSOD-Ac), increased reactive oxygen species (ROS) and the activation of hypoxia induced factor 2? (HIF2?). The activation of HIF2? is a well-established mechanism of 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 chronic As exposure is a risk factor for the development of ER(-) breast cancer via a mechanism that involves MnSOD acetylation and mitochondrial ROS. By extension, we propose that the MnSOD-Ac/HIF2? molecular signature may identify women with breast cancer that have been exposed to As and who may require personalized care for they are at increased risk of failing standard therapeutics. Also, that the MnSOD-Ac/HIF2? may be targeted to improve therapy in these women. Our aims are as follows: (1) determine if MnSOD-Ac reprograms tumor cell to stem-like (more aggressive) phenotypes associated with chemoresistance and if targeting MnSOD-Ac reverses this effect. (2) determine if low level arsenic exposure in the drinking water transforms ER+ in situ xenograph tumors developing in mice towards more pervasive phenotypes. (3) determine if there is an association between arsenic exposure and more aggressive subtypes of breast cancer with a MnSOD-Ac, or MnSOD-ROS-HIF2? molecular signature as well as if arsenic exposure promotes chemoresistance or a prevalence of aggressive ER(-) phenotypes.