Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling.
Cancer cells require sustained oncogenic signaling in order to maintain their malignant properties. It is, however, unclear whether they possess other dependencies that can be exploited therapeutically. We report here that in a large fraction of human breast cancers, the gene encoding focal adhesion kinase (FAK), a core component of integrin signaling, was amplified and FAK mRNA was overexpressed. A mammary gland-specific deletion of Fak in mice did not seem to affect normal mammary epithelial cells, and these mice were protected from tumors initiated by the polyoma middle T oncoprotein (PyMT), which activates Ras and PI3K. FAK-deficient PyMT-transformed cells displayed both growth arrest and apoptosis, as well as diminished invasive and metastatic capacity. Upon silencing of Fak, mouse mammary tumor cells transformed by activated Ras became senescent and lost their invasive ability. Further, Neu-transformed cells also underwent growth arrest and apoptosis if integrin beta4-dependent signaling was simultaneously inactivated. Human breast cancer cells carrying oncogenic mutations that activate Ras or PI3K signaling displayed similar responses upon silencing of FAK. Mechanistic studies indicated that FAK sustains tumorigenesis by promoting Src-mediated phosphorylation of p130Cas. These results suggest that FAK supports Ras- and PI3K-dependent mammary tumor initiation, maintenance, and progression to metastasis by orchestrating multiple core cellular functions, including proliferation, survival, and avoidance of senescence.
Pylayeva
Yuliya
Y
Cell Biology Program, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA. pylayy01@nyumc.org
Gillen
Kelly M
KM
Gerald
William
W
Beggs
Hilary E
HE
Reichardt
Louis F
LF
Giancotti
Filippo G
FG
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000633:toxicity; D001943:Breast Neoplasms / Q000201:enzymology / Q000209:etiology*; D016922:Cellular Senescence; D050719:Crk-Associated Substrate Protein / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology*; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000209:etiology*; D051379:Mice; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D000952:Antigens, Polyomavirus Transforming; C493842:Bcar1 protein, mouse; D050719:Crk-Associated Substrate Protein; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases