Tyrosine phosphorylation-dependent signaling, as mediated by members of the EGF receptor (EGFR) family (ErbB1-4) of protein tyrosine kinases (PTKs), Src family PTKs (SFKs) and cytokines such as IL-6 that signal via STAT3, is critical to the development and progression of many human breast cancers. The 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 signalling, whereas TCPTP deficiency in human breast cancer cell lines enhances SFK and STAT3 signalling. 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 tumour suppressor in human breast cancer.