TCPTP Regulates SFK and STAT3 Signaling and Is Lost in Triple-Negative Breast Cancers

ABSTRACTTyrosine 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 linesin vitroand that TCPTP protein is absent in a large proportion of “triple-negative” primary human breast cancers. Homozygous TCPTP deficiency in murine mammary fat padsin vivois 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 growthin vitroand xenograft growthin vivo. These studies establish TCPTP's potential to serve as a tumor suppressor in human breast cancer.