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

TitleActivation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase.
Publication TypeJournal Article
Year of Publication2011
AuthorsSun, 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
JournalCell
Volume144
Issue5
Pagination703-18
Date Published2011 Mar 04
ISSN1097-4172
KeywordsBreast 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.

DOI10.1016/j.cell.2011.02.003
Alternate JournalCell
PubMed ID21376233
PubMed Central IDPMC6014607
Grant ListHG3456 / HG / NHGRI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
P50 CA058183 / CA / NCI NIH HHS / United States
R01 HG003456 / HG / NHGRI NIH HHS / United States