title: SHP2 acts both upstream and downstream of multiple receptor tyrosine kinases to promote basal-like and triple-negative breast cancer.
abstract: BACKGROUND
  Dysregulated receptor tyrosine kinase (RTK) signaling is a common occurrence in basal-like and triple-negative breast cancer (BTBC). As a result, RTK-targeting therapies have been initiated but proved difficult, mainly owing to the multiplicity of dysregulated RTKs. Hence, targeting master regulators of RTK signaling might alleviate this obstacle. Before that, however, defining the mechanism of such molecules is required. In this report, we show that the Src homology phosphotyrosyl phosphatase 2 (SHP2) is a master regulator of RTK expression and signaling in BTBC.
  
  
  METHODS
  Xenograft tumor growth studies were used to determine the effect of SHP2 inhibition on tumorigenesis and/or metastasis. Cell proliferation rate, anchorage-independent growth, mammosphere formation, and ALDEFLUOR assays were used to compare the relative functional importance of SHP2 and the epidermal growth factor receptor (EGFR) in BTBC cells. Immunohistochemistry and immunofluorescence analyses were used to determine the state of SHP2 and EGFR coexpression in BTBC. Analysis of mitogenic and cell survival signaling was performed to show SHP2's role in signaling by multiple RTKs.
  
  
  RESULTS
  Inhibition of SHP2 in BTBC cells suppresses their tumorigenic and metastatic properties. Because EGFR is the most commonly dysregulated RTK in BTBC, we first tested the effect of SHP2 inhibition on EGFR signaling and found that SHP2 is important not only for mediation of the Ras/extracellular signal-regulated kinase and the phosphatidyl inositol 3-kinase/Akt signaling pathways but also for the expression of the receptor itself. The existence of a tight association between SHP2 and EGFR expression in tumors and cell lines further suggested the importance of SHP2 in EGFR expression. Comparison of relative biological significance showed the superiority of SHP2 inhibition over that of EGFR, suggesting the existence of additional RTKs regulated by SHP2. Indeed, we found that the expression as well as the signaling efficiency of c-Met and fibroblast growth factor receptor 1, two other RTKs known to be dysregulated in BTBC, are SHP2-dependent. To our knowledge, this is the first demonstration of SHP2 acting both upstream and downstream of RTKs to promote signaling.
  
  
  CONCLUSIONS
  SHP2 upregulates the expression and signaling of multiple RTKs to promote BTBC. These findings provide a mechanistic explanation for the superiority of SHP2 inhibition in BTBC.
authors.affiliation: Department of Biochemistry, West Virginia University, Morgantown, WV, 26506, USA.
authors.forename: Fatimah
authors.initials: F
authors.lastname: Matalkah
authors.affiliation: Department of Biochemistry, West Virginia University, Morgantown, WV, 26506, USA.
authors.forename: Elisha
authors.initials: E
authors.lastname: Martin
authors.affiliation: Department of Biochemistry, West Virginia University, Morgantown, WV, 26506, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, West Virginia University, Morgantown, WV, 26506, USA. yagazie@hsc.wvu.edu.|The Marry Babb Randolph Cancer Center, School of Medicine, West Virginia University, Morgantown, WV 26506, USA. yagazie@hsc.wvu.edu.
authors.forename: Yehenew M
authors.initials: YM
authors.lastname: Agazie
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000096:biosynthesis / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11