In utero exposure to alcohol-induced mammary stem cell deregulation and tumor risk later in life.

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PROJECT SUMMARY Our long-term goal is to understand the mechanisms of in utero exposure to alcohol in breast cancer etiology and develop preventative strategies. The objective of this project is to investigate the mechanisms of in utero exposure to alcohol-induced mammary tumor development with a focus on stem cell deregulation. Maternal alcohol use during pregnancy has a profound impact on fetal development and disease risk later in life. Increasing evidence indicates that in utero exposure to certain environmental factors is associated with amplified breast cancer risk. Previous studies also suggest a link between in utero exposure to alcohol (IUE alcohol) and increased mammary tumors based on carcinogen-induced models. The underlying mechanisms, however, remain unclear. We will study the effects of IUE alcohol on mammary tumor risk using the MMTV- erbB2 transgenic mouse model. Our preliminary data demonstrated that IUE alcohol induces significant pro- estrogenic changes in mammary development and increased tumor multiplicity in this model system. Microarray analysis showed that IUE alcohol induces distinctive gene expression associated with receptor tyrosine kinase signaling pathways in the premalignant mammary tissues. We also found that terminal end bud numbers and estrogen receptor (ER) and erbB2 pathway signaling were modified in the mammary glands in response to IUE alcohol. Upon examining the effects of IUE alcohol on mammary epithelial cell differentiation, we found that IUE alcohol induced the expansion of the basal/myoepithelial and luminal subpopulations in pubertal mammary glands. To advance our understanding of IUE alcohol-associated breast cancer risk, we propose to investigate the mechanisms of IUE alcohol-induced deregulation of mammary stem cells (MaSCs)/tumor-initiating cells (TICs) and crosstalk between ER and erbB2 pathways in mammary tumor development in MMTV-erbB2 transgenic mice. Supported by our preliminary studies, we hypothesize that IUE alcohol promotes mammary tumor risk through the upregulation of ER-erbB2 crosstalk and the consequent deregulation of MaSCs/progenitor cells, which leads to cancer stem cell/TIC expansion and tumor development. The specific aims are: 1) To determine the effects of IUE alcohol on MaSC and TIC expansion and function in mammary tissues and tumors from MMTV-erbB2 mice and 2) To investigate the role of IUE alcohol-induced ER and Sox2 upregulation in the deregulation of MaSCs and TICs in mammary tissues from erbB2 mice. With this clinically relevant mouse model, significant health concern, and novel approaches, the results from this project are expected to have a profound impact on breast cancer etiology and prevention.