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- Title
p130Cas alters the differentiation potential of mammary luminal progenitors by deregulating c-Kit activity.
- Authors
Tornillo, Giusy; Elia, Angela Rita; Castellano, Isabella; Spadaro, Michela; Bernabei, Paola; Bisaro, Brigitte; Camacho-Leal, Maria del Pilar; Pincini, Alessandra; Provero, Paolo; Sapino, Anna; Turco, Emilia; Defilippi, Paola; Cabodi, Sara
- Abstract
It has recently been proposed that defective differentiation of mammary luminal progenitors predisposes to basal-like breast cancer. However, the molecular and cellular mechanisms involved are still unclear. Here, we describe that the adaptor protein p130Cas is a crucial regulator of mouse mammary epithelial cell (MMEC) differentiation. Using a transgenic mouse model, we show that forced p130Cas overexpression in the luminal progenitor cell compartment results in the expansion of luminal cells, which aberrantly display basal cell features and reduced differentiation in response to lactogenic stimuli. Interestingly, MMECs overexpressing p130Cas exhibit hyperactivation of the tyrosine kinase receptor c-Kit. In addition, we demonstrate that the constitutive c-Kit activation alone mimics p130Cas overexpression, whereas c-Kit downregulation is sufficient to re-establish proper differentiation of p130Cas overexpressing cells. Overall, our data indicate that high levels of p130Cas, via abnormal c-Kit activation, promote mammary luminal cell plasticity, thus providing the conditions for the development of basal-like breast cancer. Consistently, p130Cas is overexpressed in human triple-negative breast cancer, further suggesting that p130Cas upregulation may be a priming event for the onset of basal-like breast cancer. S TEM C ells 2013;31:1422-1433
- Subjects
CELL differentiation; PROGENITOR cells; EPITHELIAL cells; GENE expression; CELL compartmentation; PROTEIN-tyrosine kinases; LABORATORY mice
- Publication
Stem Cells, 2013, Vol 31, Issue 7, p1422
- ISSN
1066-5099
- Publication type
Article
- DOI
10.1002/stem.1403