| Title | Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase. |
| Publication Type | Journal Article |
| Year of Publication | 2011 |
| Authors | Sun, T, Aceto, N, Meerbrey, KL, Kessler, JD, Zhou, C, Migliaccio, I, Nguyen, DX, Pavlova, NN, Botero, M, Huang, J, Bernardi, RJ, Schmitt, E, Hu, G, Li, MZ, Dephoure, N, Gygi, SP, Rao, M, Creighton, CJ, Hilsenbeck, SG, Shaw, CA, Muzny, DM, Gibbs, RA, Wheeler, DA, C Osborne, K, Schiff, R, Bentires-Alj, M, Elledge, SJ, Westbrook, TF |
| Journal | Cell |
| Volume | 144 |
| Issue | 5 |
| Pagination | 703-18 |
| Date Published | 2011 Mar 04 |
| ISSN | 1097-4172 |
| Keywords | Breast Neoplasms, Cell Line, Tumor, Cell Transformation, Neoplastic, ErbB Receptors, Female, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, MicroRNAs, Mutation, Neoplasm Metastasis, Protein Processing, Post-Translational, Protein Tyrosine Phosphatase, Non-Receptor Type 12, Tumor Suppressor Proteins |
| Abstract | Among breast cancers, triple-negative breast cancer (TNBC) is the most poorly understood and is refractory to current targeted therapies. Using a genetic screen, we identify the PTPN12 tyrosine phosphatase as a tumor suppressor in TNBC. PTPN12 potently suppresses mammary epithelial cell proliferation and transformation. PTPN12 is frequently compromised in human TNBCs, and we identify an upstream tumor-suppressor network that posttranscriptionally controls PTPN12. PTPN12 suppresses transformation by interacting with and inhibiting multiple oncogenic tyrosine kinases, including HER2 and EGFR. The tumorigenic and metastatic potential of PTPN12-deficient TNBC cells is severely impaired upon restoration of PTPN12 function or combined inhibition of PTPN12-regulated tyrosine kinases, suggesting that TNBCs are dependent on the proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor and provide a rationale for combinatorially targeting proto-oncogenic tyrosine kinases in TNBC and other cancers based on their profile of tyrosine-phosphatase activity. |
| DOI | 10.1016/j.cell.2011.02.003 |
| Alternate Journal | Cell |
| PubMed ID | 21376233 |
| PubMed Central ID | PMC6014607 |
| Grant List | / HHMI / Howard Hughes Medical Institute / United States HG3456 / HG / NHGRI NIH HHS / United States P30 CA125123 / CA / NCI NIH HHS / United States P50 CA058183 / CA / NCI NIH HHS / United States R01 HG003456 / HG / NHGRI NIH HHS / United States |