c-ERBB2/HER2 is a gene that is found overexpressed in ~25% of mammary tumours, and defines the molecular signature of one of the breast cancer subtypes: the HER2-positive tumour subtype. However, the role of the c-ErbB2 tyrosine kinase and the stem cell of origin of HER2-positive breast cancers are poorly understood. Our project aims to study the relationship between c-ErbB2 function and normal and tumour stem cells, as well as on the origin and development of HER2-positive tumours. First, we will study the effects of overexpressing c-ErbB2, or of knocking its expression down, on in vivo mouse mammary epithelial biology. Lentiviral transduction of primary mouse mammary epithelial cells combined with cleared fat pad transplantation and flow cytometric analysis of the resulting outgrowths will be used to study the role of the protein in the normal gland. Second, tumour cells will be isolated from mouse c-ErbB2/neu tumour models and limited dilution transplant assays of cell subpopulations will be used to identify tumour stem cells. Last, a Stop-Flox-Neu mouse model will be combined with transgenic mice carrying the Cre recombinase under different cell-type specific promoters to ask whether activity of c-ErbB2/neu in different subpopulations results in different tumour types with greater or lesser resemblance to human HER2-positive tumours. Identifying the origin of HER2 tumours may be critical for understanding resistance to HER2-targeted therapies as tumours of differing cellular origin may have distinct mechanisms of resistance. The knowledge of the relationships and interactions between HER2 and mammary stem/progenitor cells will be a key aspect of understanding both the role of HER2 in the normal breast and how its over-expression drives breast cancer.
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