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Characterization of myoepithelial differentiation in basal-like breast cancer cells

Final Report Summary - BASAL BREAST CANCER (Characterization of myoepithelial differentiation in basal-like breast cancer cells)

Breast cancer is the most frequent tumour type in European women, accounting for 25 % of all female cancers. Breast carcinomas arise from the malignant transformation of cells within the glandular compartments called 'ductal-lobular units'. These structures are mainly composed by an inner layer of secretory epithelial (luminal) cells and an outer of contractile myoepithelial (basal) cells, and are surrounded by supportive tissue (stroma). In addition, the normal breast contains pluripotent stem cells that can give rise to the differentiated luminal or myoepithelial cells and thus have the potential to regenerate a complete mammary gland.

Breast carcinomas can be divided into two major subgroups according to their distinct molecular features: those with the 'luminal phenotype' express mainly luminal epithelial markers, whereas 'basal' ones exhibit mixed expression of myoepithelial and luminal markers. A similar mixture of luminal and myoepithelial markers has been described in the stem cells of the normal mammary gland. These observations gave rise to the question of whether basal tumours may originate from the malignant transformation of stem cells that have undergone a block in their differentiation program rather than from myoepithelial cells. As the presence of cancer cells with stem cell properties within breast tumours has been proposed to promote resistance to chemotherapy and tumour recurrence, and basal tumours show poor prognosis, it is imperative to address if this tumour type originate from malignant stem cells.

To test this hypothesis, this project had two main aims to:
a) determine whether basal cell lines (normal and tumourigenic) show stem cell features; and
b) to assess the capacity of basal cells to differentiate to myoepithelial cells, to evaluate if basal-like carcinomas have a block in their differentiation program.

In this programme of work we demonstrated that basal cell lines contained subpopulations with stem cell features. These stem cells were proved to have a partial, but not complete, capacity to differentiate towards luminal or myoepithelial lineages, thus indicating that basal tumours have a block in their differentiation program. In addition, we observed that basal cells showed an intrinsic ability to convert into fibroblastic (stromal-like) cells. During this conversion of basal cells into fibroblastic cells some myoepithelial traits were lost, suggesting that this process reflects aberrant myoepithelial differentiation.

Further investigations into the molecular mechanisms involved in the maintenance of stem cell features and the differentiation potential of basal cells led us to identify a number of molecules (the factors Slug, Twist and Zeb1) as key factors with the potential to control the basal phenotype. These factors were demonstrated to be specifically expressed in normal and tumourigenic basal cells compared to luminal cells. Finally, we demonstrated that the presence of these factors were involved in maintaining an undifferentiated (stem-cell like) phenotype in the basal cells and inhibiting luminal differentiation.

In conclusion, the results obtained in this project demonstrate that basal cell lines show intrinsic phenotypic heterogeneity and contain subpopulations with undifferentiated 'stem cell-like' features. These data provide an explanation for the mixed expression of luminal and myoepithelial markers observed in human basal tumours. Moreover these data suggest that basal cancer cells with stem cell features may be unable to fully differentiate into myoepithelial cells, but may instead generate fibroblastic cells. Finally we have provided evidence that a series of specific factors (Slug, Twist, and Zeb1) control the maintenance of an undifferentiated (stem-cell like) phenotype in normal and cancer basal cells.