Protein Tyrosine Phosphatase µ (PTP µ or PTPRM), a Negative Regulator of Proliferation and Invasion of Breast Cancer Cells, Is Associated with Disease Prognosis

Abstract

BackgroundPTPRM has been shown to exhibit homophilic binding and confer cell-cell adhesion in cells including epithelial and cancer cells. The present study investigated the expression of PTPRM in breast cancer and the biological impact of PTPRM on breast cancer cells.DesignExpression of PTPRM protein and gene transcript was examined in a cohort of breast cancer patients. Knockdown of PTPRM in breast cancer cells was performed using a specific anti-PTPRM transgene. The impact of PTPRM knockdown on breast cancer was evaluated using in vitro cell models.ResultsA significant decrease of PTPRM transcripts was seen in poorly differentiated and moderately differentiated tumours compared with well differentiated tumours. Patients with lower expression of PTPRM had shorter survival compared with those which had a higher level of PTPRM expression. Knockdown of PTPRM increased proliferation, adhesion, invasion and migration of breast cancer cells. Furthermore, knockdown of PTPRM in MDA-MB-231 cells resulted in increased cell migration and invasion via regulation of the tyrosine phosphorylation of ERK and JNK.ConclusionsDecreased expression of PTPRM in breast cancer is correlated with poor prognosis and inversely correlated with disease free survival. PTPRM coordinated cell migration and invasion through the regulation of tyrosine phosphorylation of ERK and JNK.

Regulation of development and cancer by the R2B subfamily of RPTPs and the implications of proteolysis

“…Full-length PTPμ functions as a tumor suppressor in breast cancer and glioma [74, 75]. The PTPRM promoter is hypermethylated in sporadic colorectal cancer [68], and the PTPRM gene is frequently mutated in HNSCC [67].…”

“…The PTPRM promoter is hypermethylated in sporadic colorectal cancer [68], and the PTPRM gene is frequently mutated in HNSCC [67]. Functionally, reduced levels of PTPμ mRNA in breast cancer patients are associated with poor prognosis and shorter disease free survival time [74]. Similarly, less full-length PTPμ protein is observed in high-grade brain tumor glioblastoma multiforme (GBM) than in lower grade astrocytomas or in noncancerous brain tissue [75].…”

“…Similarly, less full-length PTPμ protein is observed in high-grade brain tumor glioblastoma multiforme (GBM) than in lower grade astrocytomas or in noncancerous brain tissue [75]. Concomitant with the reduction of PTPμ protein and/or transcript levels is an increase in tumor cell invasiveness, motility and cell growth [74, 75]. The identity of some of the downstream signaling defects predicted to occur in cancer cells following PTPμ disruption are known.…”

“…For example, in glioma cells, PLCγ1 activity is downstream of PTPμ signaling and PLCγ1 activity is required for mediating cancer cell migration in the absence of PTPμ protein [45]. In breast cancer cells, ERK and JNK activity are required to promote migration when PTPμ expression is reduced [74]. …”

Expression array analysis of the hepatocyte growth factor invasive program

“…Similarly, the adhesion adapter AKAP12 repressed prostate metastasis and cell motility by sequestering Src away from FAK-associated adhesion and signaling complexes [99][100][101], suggesting that AKAP12 suppression by HGF ligands is likely to promote PC3M invasion and metastasis. HGF-suppression of the protein tyrosine phosphatase encoded by PTPRM, a negative regulator of invasion by glioma [102] and breast cancer [103] cells, and upregulation of the integrin adapter encoded by NEDD9, which promotes epithelial-to-mesenchymal transition and invasion by PCa cells [104,105], also predict enhancement of PC3M invasiveness.…”