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.

PTPRO Promotes Oxidized Low-Density Lipoprotein Induced Oxidative Stress and Cell Apoptosis through Toll-Like Receptor 4/Nuclear Factor κB Pathway

“…As an integral membrane protein with its full isoform (PTPRO) expressed in many parenchymal cells (including lung, liver, and breast) and truncated isoform identified in inflammatory cells, such as macrophages and lymphocytes, PTPRO has been verified as a functional participator involved in the development of several tumors and inflammatory diseases [16-19]. Former studies suggested that PTPRO played critical roles in acute inflammation mediated by T lymphocytes [20] and macrophages [17] via activation of NF-kB signaling pathway.…”

The oncogenic roles of nuclear receptor coactivator 1 in human esophageal carcinoma

“…The cylindrical tumor cores were punched and transferred to the recipient block using a 2.0‐mm diameter precision punch. Blocks of the tissue microarray (TMA) were cut into 4‐μm sections and processed for IHC as described previously . TMA slides were incubated with anti‐NCOA1 antibody (sc‐8995, Santa Cruz) at room temperature for 1 hour followed by incubation with the HRP‐conjugated secondary antibody at room temperature for 30 minutes.…”

“…Blocks of the tissue microarray (TMA) were cut into 4-μm sections and processed for IHC as described previously. [42][43][44][45] TMA slides were incubated with anti-NCOA1 antibody (sc-8995, Santa Cruz) at room temperature for 1 hour followed by incubation with the HRP-conjugated secondary antibody at room temperature for 30 minutes. Immunostaining was visualized by 3, 3′-diaminobenzidine (DAB), and the cell nuclei were counterstained by hematoxylin.…”

“…jsp). 42,44 2.11 | Statistical analysis SPSS 13.0 (SPSS Inc, Chicago, IL) was used to analyze the data. The correlation between the expression of NCOA1 and clinic-pathological features of ESCC patients was examined by chi-square test.…”

Potentially functional variants in lncRNAs are associated with breast cancer risk in a Chinese population

“…Moreover, in the present study, we observed that AC104135.3 was co‐expressed with the well‐known oncogene ERBB2 . ERBB2 overexpression occurs in approximately 30% of breast cancer patients and promotes the proliferation or/and metastasis of breast cancer cells through cross‐talk with multiple oncogenic pathways . Interestingly, in the stratification analysis, we observed that the protective effect of rs11471161 in breast cancer was significant in ERBB2‐negative status (Table ).…”