Arsenic Repression of GADD153 and Breast Cancer

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DESCRIPTION (provided by applicant): Arsenic is a well-known human carcinogen. Previous studies including human population studies provide an extensive and important link between the arsenic exposure and development of breast cancer. These studies suggest that arsenic accumulates in breast tissues and acts as an endocrine disruptor to promote development of breast cancer. Arsenic is one of the few human carcinogens that do not induce tumors in laboratory animals. Therefore, development of models for arsenic-induced breast cancer is critical for understanding the mechanism(s) underlying the tumorigenic process. We have developed a mammary epithelial cell model for arsenic-induced cancer. To replicate normal field exposure conditions, we exposed mammary epithelial cells to a low dose of arsenic for several months. We discovered that a five month continuous exposure of mammary epithelial cells results in increased cell proliferation, increased wound healing, increased anchorage independent growth, as well as increased matrigel invasion. These studies suggest a tumorigenic transformation of mammary epithelial cells by exposure to arsenic. Mitochondria control cell growth and cell death. Mitochondria also perform other cellular functions including ATP production via mitochondrial oxidative phosphorylation (mtOXPHOS). Consistent with this finding arsenic-transformed cells show 1) altered mtOXPHOS Complex I and IV activities; 2) an altered expression of subunit NDUFB8 comprising mtOXPHOS Complex I; and 3) altered expression of COXII subunit comprising mtOXPHOS complex IV. Interestingly, our study suggests that arsenic-treatment did not induce changes in mtOXPHOS Complex II and III activities. These preliminary studies revealed that arsenic targets mitochondria and induces mitochondrial stress. Recent studies suggest that human cells contain mitochondria specific stress response pathway in which transcription factor GADD153 (also known as CHOP or DDIT3) plays a key role. We measured the expression of GADD153 and found that arsenic represses GADD153 expression. GADD153 is described to play a critical role in cell death and suppression of GADD153 expression is known to protect cells from cell death. However, GADD153's role in arsenic induced carcinogenesis is unknown. We hypothesize that arsenic represses expression of GADD153/CHOP/DDIT3 to protect cells from arsenic induced cell death which contributes to tumorigenic transformation of mammary epithelial cells induced by arsenic. To address this hypothesis we will: Aim 1: Determine a role for GADD153 in protection against cell death and mitochondrial stress induced by arsenic. Aim 2: Determine whether arsenic repression of GADD153 expression contributes to tumorigenic transformation of breast epithelial cells in vitro and in vivo in mouse xenograft model. The proposed studies should provide insight in to the mechanism involved in arsenic induced breast tumorigenesis.