# Alcohol-Associated Toxicity and Genomic Instability of Mammary Stem Cells

> **NIH NIH U54** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $33,428

## Abstract

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.

## Key facts

- **NIH application ID:** 10894187
- **Project number:** 5U54AA030463-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** XIAOHE YANG
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $33,428
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894187

## Citation

> US National Institutes of Health, RePORTER application 10894187, Alcohol-Associated Toxicity and Genomic Instability of Mammary Stem Cells (5U54AA030463-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10894187. Licensed CC0.

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