Environmental inorganic arsenic (iAs) is a class I human carcinogen with established roles in promoting skin, colon, bladder and kidney cancers. The role of iAs as a breast carcinogen is less established although numerous studies have indicated that in cell cultures iAs promotes the specification of breast cancer cells towards phenotypes that are estrogen receptor negative which are more lethal as well as more challenging to treat. The molecular mechanisms involved remain unknown. Our laboratory found that iAs 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 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 iAs 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 iAs and required 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 iAs 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 exposure to iAs and breast cancer with a MnSOD-Ac, or MnSOD-ROS- HIF2? molecular signature as well as if iAs exposure promotes chemoresistance or a prevalence of aggressive ER(-) phenotypes.

Public Health Relevance

Environmental inorganic arsenic (iAs) is a class I human carcinogen with established roles in many types of cancers. In the case of breast cancer specifically, it remains unclear whether iAs is a risk factor. Nevertheless, epidemiologic data indicates that there is a 2-fold higher incidence of lethal forms of estrogen receptor negative (ER-) breast cancer in regions where iAs is endemic. This is in agreement with findings in cell culture showing that iAs promotes more aggressive tumor cell phenotypes including the conversion of ER+ into ER- cell cancer cells. The molecular mechanisms involved remain unknown. Our laboratory found that iAs activates cancer stem cell reprogramming via a mechanism that involves increased mitochondrial ROS and HIF2? activation. Hence, it is proposed that iAs drives the subtype/phenotypic specification of breast tumor cells towards ER- phenotypes that are chemoresistant and prone to recur in women with breast cancer that are or have been exposed to iAs.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZRG1)
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Reinlib, Leslie J
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Medical College of Wisconsin
Internal Medicine/Medicine
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United States
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