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 +12 more
TLDR
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.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.read more
Citations
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Materials as stem cell regulators
TL;DR: Recent evidence that shows that inherent material properties may be engineered to dictate stem cell fate decisions are discussed, and a subset of the operative signal transduction mechanisms that have begun to emerge are overviewed.
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KIT (CD117) positive breast cancers are infrequent and lack kit gene mutations
Ronald Simon,S. Panussis,Kathrin Glatz,Coya Tapia,Martina Mirlacher,Michael J. Mihatsch,Guido Sauter +6 more
TL;DR: Overall, the data show that a high level of KIT expression occurs infrequently in breast cancer, and KIT-positive breast cancers may not reflect "KIT up-regulation" because KIT is also expressed in normal breast epithelium.
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CAS proteins in health and disease: an update.
TL;DR: An update on recently published studies describing signals regulating and regulated by CAS proteins, and evidence for biological activity of CAS proteins in normal development, cancer, and other pathological conditions is provided.
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Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells.
Giusy Tornillo,Catherine Knowlson,Howard Kendrick,Joe Cooke,Hasan Mirza,Iskander Aurrekoetxea-Rodríguez,Maria dM Vivanco,Niamh E. Buckley,Annita Grigoriadis,Matthew J. Smalley +9 more
TL;DR: It is demonstrated LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress and dual mechanisms—uncoupling from upstream signals and splice isoform ratios—drive the activity of LYN in aggressive breast cancers.
CAS Proteins in Health and Disease: An Update Anna S. Nikonova
TL;DR: In this article, the authors provide an update on recently published studies describing signals regulating and regulated by scaffolding proteins, and evidence for biological activity of CAS proteins in normal development, cancer, and other pathological conditions.
References
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Journal ArticleDOI
p130Cas as a New Regulator of Mammary Epithelial Cell Proliferation, Survival, and HER2-Neu Oncogene–Dependent Breast Tumorigenesis
Sara Cabodi,Agata Tinnirello,Paola Di Stefano,Brigitte Bisaro,Elena Ambrosino,Isabella Castellano,Anna Sapino,Riccardo Arisio,Federica Cavallo,Guido Forni,Marina A. Glukhova,Lorenzo Silengo,Fiorella Altruda,Emilia Turco,Guido Tarone,Paola Defilippi +15 more
TL;DR: Findings provide evidences for a role of p130Cas as a positive regulator of both proliferation and survival in normal and transformed mammary epithelial cells.
Journal Article
Growth factor requirements and basal phenotype of an immortalized mammary epithelial cell line.
James DiRenzo,Sabina Signoretti,Noriaki Nakamura,Ramon Rivera-Gonzalez,William R. Sellers,Massimo Loda,Myles Brown +6 more
TL;DR: Evidence is presented that the overexpression of human telomerase reverse transcriptase was sufficient to extend the life span of the cells and allow for additional events that lead to immortalization, and that the immortalization of basal epithelial cells of the mammary gland may be an early step in the initiation of a subset of breast cancers with a basal epithelium phenotype.
Journal ArticleDOI
Nestin is expressed in the basal/myoepithelial layer of the mammary gland and is a selective marker of basal epithelial breast tumors.
Hua Li,Pratima Cherukuri,Na Li,Victoria H. Cowling,Michael J. Spinella,Michael D. Cole,Andrew K. Godwin,Wendy A. Wells,James DiRenzo +8 more
TL;DR: Evidence is presented that nestin, a previously described marker of regenerative cells in diverse tissues, is expressed in the regenerative compartment of the normal human mammary gland and is identified as a selective marker of the basal breast cancer phenotype, which displays features of mammary progenitors.
Journal ArticleDOI
Elf5 regulates mammary gland stem/progenitor cell fate by influencing notch signaling.
Rumela Chakrabarti,Rumela Chakrabarti,Yong Wei,Rose-Anne Romano,Christina DeCoste,Yibin Kang,Satrajit Sinha +6 more
TL;DR: It is demonstrated that in addition to regulating terminal differentiation of alveolar cells, Elf5 also plays a critical role in determining cell fate and in regulating the stem/progenitor function of the mammary epithelium.
Journal ArticleDOI
c-Kit is required for growth and survival of the cells of origin of Brca1 -mutation-associated breast cancer
TL;DR: The c-Kit signalling network has potential as a target for therapy and/or prevention in BRCA1-associated breast cancer and is critical for mammary progenitor survival and proliferation.
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