Grant Number:
Principal Investigator:
Bonini, Marcelo G
Institution:
University of Illinois at Chicago
Most Recent Award Year:
2017
Exposures:
Metals:
Arsenic
Health Outcomes:
Cancer Outcomes:
ER-negative breast cancer
Biological Sample:
Breast tumor/cancer cells
Genes or Other DNA Products Studied:
Manganese superoxide dismutase mutant form (MnSOD-K68Q) that cannot be acetylated; Hypoxia-induced factor 2 (HIF2α)
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 2α (HIF2α). The activation of HIF2α 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/HIF2α 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/HIF2α 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-HIF2α molecular signature as well as if arsenic exposure promotes chemoresistance or a prevalence of aggressive ER(-) phenotypes.
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Related NIEHS-Funded Study Populations
Health Effects of Arsenic Longitudinal Study (HEALS)
Principal Investigator:
Ahsan, Habibul; Graziano, Joseph
| Study Population Page Study Population c63
Institution:
University of Chicago
Location:
Araihazar, Bangladesh
Number of Participants::
~35,000 recruited; Recruitment goal of 50,000
Brief Description::
This large prospective cohort study is based on individual-level data from a population exposed to a wide range of inorganic arsenic from drinking water in Araihazar, Bangladesh. Since 2000, the study has recruited more than 35,000 men and women with extensive questionnaire data, biological samples, drinking water samples, and diagnostic/clinical data.