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 |
Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase.
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