Activation of Multiple Proto-oncogenic Tyrosine Kinases in Breast Cancer via Loss of the PTPN12 Phosphatase

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• 作者：Tingting Sun¹ ; Nicola Aceto¹⁰ ; ¹⁴ ; Kristen  ; L. Meerbrey¹ ; ² ; ¹⁴ ; Jessica  ; D. Kessler¹ ; ² ; Chunshui Zhou¹¹ ; Ilenia Migliaccio⁶ ; Don  ; X. Nguyen¹³ ; Natalya  ; N. Pavlova¹¹ ; Maria Botero⁶ ; Jian Huang⁶ ; Ronald  ; J. Bernardi³ ; Earlene Schmitt¹ ; ² ; Guang Hu¹¹ ; Mamie Z. Li¹¹ ; Noah Dephoure¹² ; Steven  ; P. Gygi¹² ; Mitchell Rao² ; Chad  ; J. Creighton⁴ ; ⁵ ; Susan  ; G. Hilsenbeck⁴ ; ⁵ ; Chad  ; A. Shaw² ; Donna Muzny⁹ ; Richard  ; A. Gibbs² ; ⁵ ; ⁹ ; David  ; A. Wheeler⁵ ; ⁹ ; C.  ; Kent Osborne⁵ ; ⁶ ; ⁷ ; ⁸ ; Rachel Schiff⁵ ; ⁶ ; ⁷ ; ⁸ ; Mohamed Bentires-Alj¹⁰ ; ¹⁵ ; Stephen  ; J. Elledge¹¹ ; ¹⁵ ; Thomas  ; F. Westbrook¹ ; ² ; ³ ; ⁵ ; ^{thomasw@bcm.edu}
• 刊名：Cell
• 出版年：2011
• 出版时间：4 March 2011
• 年：2011
• 卷：144
• 期：5
• 页码：703-718
• 全文大小：1634 K

文摘

Summary

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.