title: p130Cas alters the differentiation potential of mammary luminal progenitors by deregulating c-Kit activity.
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.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Italy.
authors.forename: Giusy
authors.initials: G
authors.lastname: Tornillo
authors.forename: Angela Rita
authors.initials: AR
authors.lastname: Elia
authors.forename: Isabella
authors.initials: I
authors.lastname: Castellano
authors.forename: Michela
authors.initials: M
authors.lastname: Spadaro
authors.forename: Paola
authors.initials: P
authors.lastname: Bernabei
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bisaro
authors.forename: Maria Del Pilar
authors.initials: Mdel P
authors.lastname: Camacho-Leal
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pincini
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.forename: Paola
authors.initials: P
authors.lastname: Defilippi
authors.forename: Sara
authors.initials: S
authors.lastname: Cabodi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002478:Cells, Cultured; D050719:Crk-Associated Substrate Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D050719:Crk-Associated Substrate Protein; D019009:Proto-Oncogene Proteins c-kit
keywords: Basal-like breast cancer; Differentiation; Mammary luminal progenitor; c-Kit; p130Cas