Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Mol Cell Biol. 2013 Feb;33(3):557-70. doi: 10.1128/MCB.01016-12. Epub 2012 Nov 19.
Tyrosine phosphorylation-dependent signaling, as mediated by members of the epidermal growth factor receptor (EGFR) family (ErbB1 to -4) of protein tyrosine kinases (PTKs), Src family PTKs (SFKs), and cytokines such as interleukin-6 (IL-6) that signal via signal transducer and activator of transcription 3 (STAT3), is critical to the development and progression of many human breast cancers. EGFR, SFKs, and STAT3 can serve as substrates for the protein tyrosine phosphatase TCPTP (PTPN2). Here we report that TCPTP protein levels are decreased in a subset of breast cancer cell lines in vitro and that TCPTP protein is absent in a large proportion of "triple-negative" primary human breast cancers. Homozygous TCPTP deficiency in murine mammary fat pads in vivo is associated with elevated SFK and STAT3 signaling, whereas TCPTP deficiency in human breast cancer cell lines enhances SFK and STAT3 signaling. On the other hand, TCPTP reconstitution in human breast cancer cell lines severely impaired cell proliferation and suppressed anchorage-independent growth in vitro and xenograft growth in vivo. These studies establish TCPTP's potential to serve as a tumor suppressor in human breast cancer.
酪氨酸磷酸化依赖性信号转导，由表皮生长因子受体 (EGFR) 家族（ErbB1 至 -4）蛋白酪氨酸激酶 (PTKs)、Src 家族 PTKs (SFKs) 和细胞因子（如白细胞介素-6 (IL-6)）介导，通过信号转导和转录激活因子 3 (STAT3) 进行信号传递，对许多人类乳腺癌的发生和发展至关重要。EGFR、SFKs 和 STAT3 可以作为蛋白质酪氨酸磷酸酶 TCPTP（PTPN2）的底物。在这里，我们报告说，在体外的一部分乳腺癌细胞系中，TCPTP 蛋白水平降低，并且在很大一部分“三阴性”原发性人乳腺癌中不存在 TCPTP 蛋白。体内小鼠乳腺脂肪垫中 TCPTP 的纯合缺失与 SFK 和 STAT3 信号的升高有关，而人乳腺癌细胞系中 TCPTP 的缺失增强了 SFK 和 STAT3 信号。另一方面，在人乳腺癌细胞系中重建 TCPTP 严重损害了细胞增殖，并抑制了体外的无锚定依赖性生长和体内的异种移植物生长。这些研究确立了 TCPTP 作为人类乳腺癌中的肿瘤抑制因子的潜力。
