Alcohol-Associated Toxicity and Genomic Instability of Mammary Stem Cells

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PROJECT SUMMARY Alcohol consumption has been associated with increased breast cancer risk. Although alcohol-associated breast carcinogenesis has been extensively studied, the mechanisms of alcohol-induced tumor initiation, especially the primary cell targets in cancerous transformation, remains unclear. Recent advances indicate that deregulation of cancer stem cells (CSCs), a small group of tumor cells with self-renewal and differentiation potential, plays a central role in cancer initiation, development, and recurrence. The effects of alcohol consumption on breast cancer stem cells have been poorly understood. Nevertheless, studies showed that alcohol-induced liver oncogenesis involves CSC promotion. Alcohol-derived acetaldehyde (AA) induces chromosome rearrangement with functional consequences in hematopoietic stem cells, suggesting that tissue stem cells may be the primary target of alcohol/AA-associated genotoxicity. Supported by our preliminary studies showing that alcohol induces DNA damage, chromosome alterations and CSC expansion in breast cancer cell lines, this project aims to study whether and how alcohol consumption promotes cancer initiation through induction of CSCs from mammary stem cells (MaSCs). We hypothesize that alcohol promotes breast cancer development through AA-mediated gene mutations and genomic instability of MaSCs, which leads to the disruption of genome integration and cancerous transformation. The underlying mechanisms involve mutation of p53, impairment of DNA repair machinery and deregulation of stemness networks. In support of this study, we have developed the MMTV- erbB2/Aldh2-/- mouse model for mammary tumorigenesis and MaSC analysis. These unique tools will facilitate our studies on AA accumulation-associated toxicity in MaSCs in vivo. The hypothesis will be tested in three specific aims. 1) To determine whether alcohol and AA exposure promotes MaSC/CSC stemness and mammary tumor development in treated animals. 2) To examine alcohol/AA-induced genomic instability in mammary tumors and MaSCs/CSCs. 3) To understand the mechanisms of alcohol/AA-mediated genomic instability and MaSC/CSC deregulation focusing on p53 pathway and Wnt/Sox2/RANKL signaling network of mammary stemness. Results from this project will advance our understanding of alcohol-induced genomic injury and MaSC mutation that lead to malignant transformation in breast cancer initiation, and identify specific regulators that mediate these genetic and functional changes of the MaSCs and CSCs. These data will be of great significance for early diagnosis and prevention of alcohol-associated breast cancer.