Iida, NaokoZou, LihuaYao, JunLu, YilingEpstein, Charles B.Natesan, SridaranMills, Gordon B.Irie, Hanna YokoShrestha, YashaswiSelfors, LauraFrye, FabianneWang, Zhigang C.Richardson, AndreaPolyak, KorneliaHahn, WilliamBrugge, Joan2013-01-182010Irie, Hanna Y., Yashaswi Shrestha, Laura M. Selfors, Fabianne Frye, Naoko Iida, Zhigang Wang, Lihua Zou, et al. 2010. PTK6 regulates IGF-1-induced anchorage-independent survival. PLoS ONE 5(7): e11729.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:10198954Background: Proteins that are required for anchorage-independent survival of tumor cells represent attractive targets for therapeutic intervention since this property is believed to be critical for survival of tumor cells displaced from their natural niches. Anchorage-independent survival is induced by growth factor receptor hyperactivation in many cell types. We aimed to identify molecules that critically regulate IGF-1-induced anchorage-independent survival. Methods and Results: We conducted a high-throughput siRNA screen and identified PTK6 as a critical component of IGF-1 receptor (IGF-1R)-induced anchorage-independent survival of mammary epithelial cells. PTK6 downregulation induces apoptosis of breast and ovarian cancer cells deprived of matrix attachment, whereas its overexpression enhances survival. Reverse-phase protein arrays and subsequent analyses revealed that PTK6 forms a complex with IGF-1R and the adaptor protein IRS-1, and modulates anchorage-independent survival by regulating IGF-1R expression and phosphorylation. PTK6 is highly expressed not only in the previously reported Her2\(^+\) breast cancer subtype, but also in high grade ER\(^+\), Luminal B tumors and high expression is associated with adverse outcomes. Conclusions: These findings highlight PTK6 as a critical regulator of anchorage-independent survival of breast and ovarian tumor cells via modulation of IGF-1 receptor signaling, thus supporting PTK6 as a potential therapeutic target for multiple tumor types. The combined genomic and proteomic approaches in this report provide an effective strategy for identifying oncogenes and their mechanism of action.en-UScell biologycell signalingoncologybreast cancerJournal Article2013-01-1810.1371/journal.pone.0011729