Expression and prognostic impact of the protein tyrosine phosphatases PRL-1, PRL-2, and PRL-3 in breast cancer

Abstract

The aim of this study was to investigate the expression of the protein tyrosine phosphatases (PTP) PRL-1, PRL-2, and PRL-3 in human breast cancer and to evaluate its clinical and prognostic significance. PRL-PTP mRNA expression was examined in malignant (n ¼ 7) and nonmalignant (n ¼ 7) cryoconserved breast tissue samples as well as in eight breast cancer cell lines by RT -PCR. Furthermore, protein expression of PRL-3 was analysed semiquantitatively by immunohistochemistry in ductal breast carcinoma in situ (n ¼ 135) and invasive breast cancer (n ¼ 147) by use of tissue microarray technology (TMA). In 24 lymph node-positive patients we selected the corresponding lymph node metastases for analysis of PRL-3 expression, and a validation set (n ¼ 99) of invasive breast cancer samples was examined. Staining results were correlated with clinicopathological parameters and long-term follow-up. PRL-3 mRNA expression was significantly higher in malignant compared to benign breast tissue. For PRL-1 and PRL-2 expression no significant differences were observed. Staining of TMAs showed PRL-3 expression in 85.9% ductal carcinoma in situ and 75.5% invasive breast carcinomas. Analysis of survival parameters revealed a shorter disease-free survival (DFS) in patients with PRL-3-positive carcinomas, and in particular a significantly shorter DFS in nodal-positive patients with PRL-3 overexpressing tumours as compared to PRL-3-negative breast carcinomas (6677 months (95% CI, 52 -80) vs 9779 months (95% CI, 79 -115); P ¼ 0.032). Moreover, we found a more frequent expression of PRL-3 in lymph node metastases as compared to the primary tumours (91.7 vs 66.7%; P ¼ 0.033). Our results suggest that PRL-3 might serve as a novel prognostic factor in breast cancer, which may help to predict an adverse disease outcome.

A role of autophagy in PTP4A3-driven cancer progression

“…[16][17][18] More importantly, PTP4A3 is upregulated in clinically malignant cancer specimens compared with their benign counterparts in multiple human cancers and is associated with poor prognosis. 12,16,19,20 Recently, endosomes were shown to play an important function in autophagy, fusing with autophagosomes prior to lysosomal fusion for cargo degradation. [21][22][23] Since PTP4A3 and its close homolog PTP4A1 both have endosomal localization, 10,24 we investigated whether they were functionally linked to autophagy.…”

Down‐modulation of keratin 8 phosphorylation levels by PRL‐3 contributes to colorectal carcinoma progression

“…Phosphatase of regenerating liver-3 (PRL-3) was identified as the only gene that is consistently overexpressed in liver metastases derived from colorectal cancer (CRC), whereas it is undetectable in normal colorectal epithelia and shows intermediate expression in advanced primary cancer. 1 Increasing evidence suggests that PRL-3 plays multiple roles in cancer migration and metastasis: PRL-3 expression is elevated in most metastatic lesions from various human malignancies including those of the colorectum, 2,3 stomach, 4 mammary gland 5 and ovary. 6 In the in vivo cancer-metastasis models, overexpression of PRL-3 in Chinese hamster ovary (CHO) cells promoted the incidence of metastasis, 7,8 and knockdown of PRL-3 expression in CRC-derived DLD-1 cells by RNA interference effectively abrogated the activities of cancer cell motility in vitro and hepatic colonization in vivo.…”

“…6 In the in vivo cancer-metastasis models, overexpression of PRL-3 in Chinese hamster ovary (CHO) cells promoted the incidence of metastasis, 7,8 and knockdown of PRL-3 expression in CRC-derived DLD-1 cells by RNA interference effectively abrogated the activities of cancer cell motility in vitro and hepatic colonization in vivo. 3 The PRL family members (PRL-1, PRL-2 and PRL-3) comprise a distinct subclass of protein tyrosine phosphatases (PTPs), 9 whereas the C(X) 5 R motif within the P-loop of the PRL-3 protein is typical for dual-specific phosphatases: It is close in structure to the Rho-type small GTP-binding protein (GTPase) Cdc42, and to phosphatase tensin homologues deleted on chromosome 10 (PTEN). 10 The catalytic domain of the PRL-3 protein is critical for its regulation of PRL-3-mediated cancer cell migration and invasion: site-directed mutagenesis experiments revealed that catalytic domain-mutants of PRL-3 (C104A) within the P-loop diminished PRL-3-induced invasion and Rho activation in CRCderived SW480 cells.…”

PRL-3 is essentially overexpressed in primary colorectal tumours and associates with tumour aggressiveness

“…Overexpression of PRL-1 and PRL-2 transformed mouse fibroblasts and hamster pancreatic epithelial cells in culture (Cates et al, 1996), and promoted tumour growth in nude mice (Diamond et al, 1994). PRL-3 gene, located in 8q24-3, has been involved in processes of migration, invasion and metastasis in different types of cancer (Miskad et al, , 2007Wu et al, 2004;Polato et al, 2005;Radke et al, 2006;Wang et al, 2006;Qian et al, 2007). Initially, specific overexpression of PRL-3 in colorectal cancer liver metastases (LMs) was observed when compared with matched primary tumours in association with gene amplification (Saha et al, 2001;Bardelli et al, 2003).…”