title: TCPTP regulates SFK and STAT3 signaling and is lost in triple-negative breast cancers.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Shields
authors.forename: Florian
authors.initials: F
authors.lastname: Wiede
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wee
authors.forename: Christine
authors.initials: C
authors.lastname: Hauser
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Zhu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Molloy
authors.forename: Sandra A
authors.initials: SA
authors.lastname: O'Toole
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Christina A
authors.initials: CA
authors.lastname: Mitchell
authors.forename: Catriona A
authors.initials: CA
authors.lastname: McLean
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; D019061:src-Family Kinases; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C516653:Ptpn2 protein, mouse