title: PTPRO represses ERBB2-driven breast oncogenesis by dephosphorylation and endosomal internalization of ERBB2.
abstract: The plasma membrane-associated tyrosine phosphatase PTPRO is frequently transcriptionally repressed in cancers and signifies poor prognosis of breast cancer patients. In this study, deletion of Ptpro in MMTV-Erbb2 transgenic mice dramatically shortened the mammary tumor latency and accelerated tumor growth due to loss of Ptpro within the breast cancer cells but not in surrounding tissue as confirmed by hetero-transplantation studies. Both in vitro and in vivo data demonstrated that the phosphatase activity was required for the inactivation of ERBB2 and its downstream signaling. PTPRO regulated the phosphorylation status of ERBB2 at Y1248. Co-immunoprecipitation and proximity ligation assay (Duolink) indicated that PTPRO directly physically interacted with ERBB2. Moreover, PTPRO phosphatase activity shortened the half-life of ERBB2 by increasing endocytotic degradation. PTPRO reexpression by demethylation treatment using 5-azacytidine reduced the proliferation and colony formation potential in ERBB2-positive breast cancer cells. Taken together, PTPRO inhibited ERBB2-driven breast cancer through dephosphorylation leading to dual effects of ERBB2 signaling suppression and endosomal internalization of ERBB2, Therefore, reexpression of PTPRO may be a potential therapy for ERBB2-overexpressing breast cancer.
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: H
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Gastroenterology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: J
authors.initials: J
authors.lastname: Gan
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: W
authors.initials: W
authors.lastname: Lin
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: L
authors.initials: L
authors.lastname: Du
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: C
authors.initials: C
authors.lastname: Ke
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Cell Biology, Xi'an Jiaotong University Suzhou Academy, Suzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University, Washington DC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.|Department of Emergency Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Yeung
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.|Department of Biotherapy, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008822:Mice, Transgenic; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D014443:Tyrosine; C508053:ERBB2 protein, human; C516888:PTPRO protein, human