Translational research in cancer is one of the thematic priorities within FP7 Health Investigation Programme. Breast cancer is the most frequent tumour type in European women. 20-25% of breast carcinomas express myoepithelial markers, thus showing the basal-like phenotype. Basal-like tumours are typically high-grade, aggressive cancers with poor prognosis. Since basal-like phenotype closely resembles that of breast pluripotent stem cells, it has been suggested that these tumours may originate from the transformation of stem cells that have undergone a block in their differentiation program. The aim of this project is to assess the capacity of basal cells to differentiate to fully functional myoepithelial cells in an attempt to uncover the molecular mechanisms regulating the cell fate decisions made by normal and cancer breast stem cells that drive them to full versus incomplete myoepithelial differentiation. To this end, cell subpopulations with bi-lineage progenitor features will be isolated from basal-like (normal and tumourigenic) breast cell lines and their ability to conduct complete myoepithelial differentiation will be tested. The differentiation process will be further characterized by gene expression profiling in order to identify novel candidate genes involved in this process. The results obtained will be translated to the study of human breast cancer by two complementary approaches: (i) in silico analysis of gene expression data from basal-like tumours, (ii) immunohistochemical studies in normal and tumour breast samples. Finally, in vitro and in vivo functional studies will be performed to further define the role of candidate genes in myoepithelial differentiation. As cancer stem cells are suggested to be resistant to chemotherapy and responsible for tumour recurrence, the possibility to differentiate basal (stem cell-like) carcinoma cells into myoepithelial cells would open new potential avenues for the therapy of these aggressive cancers.
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