P130Cas alters the differentiation potential of mammary luminal progenitors by deregulating C-Kit activity

Giusy Tornillo, Angela Rita Elia, Isabella Castellano, Michela Spadaro, Paola Bernabei, Brigitte Bisaro, Maria Del Pilar Camacho-Leal, Alessandra Pincini, Paolo Provero, Anna Sapino, Emilia Turco, Paola Defilippi, Sara Cabodi

Research output: Contribution to journalArticlepeer-review

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 reestablish 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.

Original languageEnglish
Pages (from-to)1422-1433
Number of pages12
JournalStem Cells
Volume31
Issue number7
DOIs
Publication statusPublished - Jul 2013

Keywords

  • Basal-like breast cancer
  • c-Kit
  • Differentiation
  • Mammary luminal progenitor
  • p130Cas

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

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