BASAL BREAST CANCER

Characterization of myoepithelial differentiation in basal-like breast cancer cells

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Breast cancer is the most frequent tumour type in European women. Almost a quarter of those tumours are basal and translate to high-grade, aggressive cancer.

Descrizione progetto (Article)

Breast carcinomas, arising from the malignant transformation of cells, can be divided into two major sub-groups. These sub-groups differ according to their molecular features; one is the 'luminal phenotype' and the other is 'basal'. One hypothesis proposes that the presence of stem cell properties in breast carcinomas hardens resistance to chemotherapy and promotes tumour recurrence. Research must discover if this tumour type originates from malignant stem cells as basal tumours show poor prognosis.

To this end, the Basal Breast Cancer project had two main objectives: to determine whether basal cell lines (normal and tumourigenic) show stem cell features; and to assess the extent to which basal cells can differentiate to myoepithelial cells. If basal carcinoma cells could be differentiated into myoepithelial cells, it would open up possibilities for novel new therapies of these aggressive cancers. The differentiation process involves isolation of cell sub-populations and testing of their ability to conduct complete myoepithelial differentiation.

The study followed up on this with gene expression profiling. Once complete, project results will give the opportunity to study human breast cancer in two ways: in silico analysis of gene expression data from basal-like tumours; and immunohistochemical studies in normal and tumour breast samples.

To date, results being reported reveal that basal cell lines show intrinsic phenotypic heterogeneity and contain sub-populations with undifferentiated stem cell-like features. This explains the mixed expression of luminal and myoepithelial markers seen in basal tumours. Also, data suggest that basal cancer cells with stem cell features may not be able to fully differentiate into myoepithelial cells, generating instead fibroblastic cells. Other progress reports offer evidence that a host of specific factors (Slug, Twist, and Zeb1) control the maintenance of a stem cell-like phenotype in normal and cancer basal cells.