Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling Journal Article
| Authors: | Pylayeva, Y.; Gillen, K. M.; Gerald, W.; Beggs, H. E.; Reichardt, L. F.; Giancotti, F. G. |
| Article Title: | Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling |
| Abstract: | 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 β4-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. |
| Keywords: | signal transduction; controlled study; protein expression; protein phosphorylation; oncoprotein; gene mutation; cancer growth; nonhuman; cell proliferation; mouse; animal; animals; mice; animal tissue; cell survival; cell function; gene overexpression; metastasis; gene amplification; lung neoplasms; epidermal growth factor receptor 2; animal experiment; animal model; enzyme activation; enzymology; protein tyrosine kinase; breast neoplasms; phosphatidylinositol 3 kinase; physiology; cancer invasion; lung tumor; cancer inhibition; messenger rna; cell transformation; breast tumor; 1-phosphatidylinositol 3-kinase; breast epithelium; epithelium cell; polyoma virus; ras protein; neoplasm invasiveness; gene silencing; experimental neoplasm; genes, ras; virus t antigen; antigens, polyomavirus transforming; genetic code; focal adhesion kinase; cell aging; oncogene ras; crk associated substrate protein; bcar1 protein, mouse; crk-associated substrate protein; focal adhesion protein-tyrosine kinases; mammary neoplasms, experimental |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 119 |
| Issue: | 2 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2009-02-01 |
| Start Page: | 252 |
| End Page: | 266 |
| Language: | English |
| DOI: | 10.1172/jci37160 |
| PUBMED: | 19147981 |
| PROVIDER: | scopus |
| PMCID: | PMC2631302 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 28" - "Export Date: 30 November 2010" - "CODEN: JCINA" - "Source: Scopus" |
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