世界顶级杂志《细胞》最近发表了美国哈佛大学医学院与哈尔滨医科大学专家关于PTPN12蛋白为新型抑癌基因的研究结果。该项针对三阴型乳腺癌进行的抑癌基因筛查研究，对三阴型乳腺癌靶向治疗有着重大指导意义。《细胞》杂志对该论文进行了专门评述。

据介绍，PTPN12是哈佛医学院Elledge实验室用shRNA文库技术筛选肿瘤细胞转化因子时发现的一个阳性蛋白分子。研究发现，PTPN12表达水平降低会引起正常细胞恶性生长，过量表达则可对恶性细胞生长有一定抑制效果。通过对PTPN12蛋白功能域结构分析，专家定性它是一个络氨酸去磷酸化酶。

为进一步揭示PTPN12的抑癌机制，哈医大医学遗传学研究室周春水教授利用目前国际上前沿的定量磷酸化蛋白组学技术研究发现，在PTPN12表达受到抑制时，乳腺癌的促癌基因EGFR受体家族的络氨酸磷酸化显著增强。而EGFR受体家族正是经过一系列络氨酸磷酸化而被激活，从而产生促细胞癌变效应。周春水的研究提示EGFR等促癌基因是PTPN12的体内作用靶点蛋白分子，成功地锁定了PTPN12是一种新型抑癌基因。

哈佛医学院的研究人员经过进一步研究发现，PTPN12在多种三阴型乳腺癌细胞系有功能缺失性基因突变。在60%的临床三阴型乳腺癌患者标本病理切片中，PTPN12蛋白表达低下。这些临床病例研究结果进一步支持PTPN12在三阴型乳腺癌的发生进展过程中占有重要地位。（生物谷Bioon.com）

生物谷推荐原文出处：

Cell   doi:10.1016/j.cell.2011.02.003

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

Authors

Tingting Sun, Nicola Aceto, Kristen L. Meerbrey, Jessica D. Kessler, Chunshui Zhou, Ilenia Migliaccio, Don X. Nguyen, Natalya N. Pavlova, Maria Botero, Jian Huang, Ronald J. Bernardi, Earlene Schmitt, Guang Hu, Mamie Z. Li, Noah Dephoure, Steven P. Gygi, Mitchell Rao, Chad J. Creighton, Susan G. Hilsenbeck, Chad A. Shaw, Donna Muzny, Richard A. Gibbs, David A. Wheeler, C. Kent Osborne, Rachel Schiff, Mohamed Bentires-Alj, Stephen J. Elledge, Thomas F. Westbrook

Highlights

Tyrosine phosphatase PTPN12 suppresses transformation, tumorigenesis, and metastasis

PTPN12 inhibits multiple oncogenic tyrosine kinases including HER2, EGFR, and PDGFR-β

PTPN12 is frequently inactivated in human triple negative breast cancer (TNBC)

PTPN12-deficient TNBCs can be treated with combinatorial tyrosine kinase inhibitors

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.