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Cancer Res. 2013 Sep 1;73(17):5591-602. doi: 10.1158/0008-5472.CAN-13-1351. Epub 2013 Jul 5.

Distinct FAK activities determine progenitor and mammary stem cell characteristics.

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  • 1Divisions of Molecular Medicine and Genetics and Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, and Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Abstract

Mammary stem cells (MaSC) and progenitor cells are important for mammary gland development and maintenance and may give rise to mammary cancer stem cells (MaCSC). Yet, there remains limited understanding of how these cells contribute to tumorigenesis. Here, we show that conditional deletion of focal adhesion kinase (FAK) in embryonic mammary epithelial cells (MaEC) decreases luminal progenitors and basal MaSCs, reducing their colony-forming and regenerative potentials in a cell-autonomous manner. Loss of FAK kinase activity in MaECs specifically impaired luminal progenitor proliferation and alveologenesis, whereas a kinase-independent activity of FAK supported ductal invasion and basal MaSC activity. Deficiency in luminal progenitors suppressed tumorigenesis and MaCSC formation in a mouse model of breast cancer. In contrast with the general inhibitory effect of FAK attenuation, inhibitors of FAK kinase preferentially inhibited proliferation and tumorsphere formation of luminal progenitor-like, but not MaSC-like, human breast cancer cells. Our findings establish distinct kinase-dependent and -independent activities of FAK that differentially regulate luminal progenitors and basal MaSCs. We suggest that targeting these distinct functions may tailor therapeutic strategies to address breast cancer heterogeneity more effectively.

PMID:
23832665
PMCID:
PMC3766468
DOI:
10.1158/0008-5472.CAN-13-1351
[PubMed - indexed for MEDLINE]
Free PMC Article
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