世界頂級雜志《細胞》最近發(fā)表了美國哈佛大學(xué)醫(yī)學(xué)院與哈爾濱醫(yī)科大學(xué)專家關(guān)于PTPN12蛋白為新型抑癌基因的研究結(jié)果,。該項針對三陰型乳腺癌進行的抑癌基因篩查研究，對三陰型乳腺癌靶向治療有著重大指導(dǎo)意義?！都毎冯s志對該論文進行了專門評述。
據(jù)介紹,，PTPN12是哈佛醫(yī)學(xué)院Elledge實驗室用shRNA文庫技術(shù)篩選腫瘤細胞轉(zhuǎn)化因子時發(fā)現(xiàn)的一個陽性蛋白分子,。研究發(fā)現(xiàn)，PTPN12表達水平降低會引起正常細胞惡性生長,，過量表達則可對惡性細胞生長有一定抑制效果,。通過對PTPN12蛋白功能域結(jié)構(gòu)分析，專家定性它是一個絡(luò)氨酸去磷酸化酶,。
為進一步揭示PTPN12的抑癌機制,，哈醫(yī)大醫(yī)學(xué)遺傳學(xué)研究室周春水教授利用目前國際上前沿的定量磷酸化蛋白組學(xué)技術(shù)研究發(fā)現(xiàn)，在PTPN12表達受到抑制時,，乳腺癌的促癌基因EGFR受體家族的絡(luò)氨酸磷酸化顯著增強,。而EGFR受體家族正是經(jīng)過一系列絡(luò)氨酸磷酸化而被激活，從而產(chǎn)生促細胞癌變效應(yīng),。周春水的研究提示EGFR等促癌基因是PTPN12的體內(nèi)作用靶點蛋白分子,，成功地鎖定了PTPN12是一種新型抑癌基因。
哈佛醫(yī)學(xué)院的研究人員經(jīng)過進一步研究發(fā)現(xiàn),，PTPN12在多種三陰型乳腺癌細胞系有功能缺失性基因突變,。在60%的臨床三陰型乳腺癌患者標本病理切片中，PTPN12蛋白表達低下,。這些臨床病例研究結(jié)果進一步支持PTPN12在三陰型乳腺癌的發(fā)生進展過程中占有重要地位,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
