Clinical importance of phosphatase of regenerating liver-3 expression in breast cancer

Department of Medical Oncology, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey, .
Clinical and Translational Oncology (Impact Factor: 2.08). 07/2012; 14(12). DOI: 10.1007/s12094-012-0880-5
Source: PubMed


BACKGROUND: Several biomarkers have been previously studied for breast cancer to define risk of recurrence and metastasis. Phosphatase of regenerating liver-3 (PRL-3) is one of them. High PRL-3 expression has been found to be correlated with axillary lymph node metastasis and survival in breast cancer. Herein, we evaluated the prognostic significance of PRL-3 expression and the relationship between PRL-3 and other clinicopathological factors. METHODS: PRL-3 expression was analyzed immunohistochemically in 122 invasive breast cancer tissues. We evaluated the correlation between PRL-3 and other clinicopathological factors by χ² test. Kaplan-Meier test and log rank method were used to define prognostic importance of PRL-3 expression. RESULTS: Of 122 breast cancer tumor samples, 46 (37.7 %) were negative while 76 (62.3 %) were positive in respect to PRL-3 expression. There was significant correlation between PRL-3 expression and other clinicopathological factors, such as histology, lymphovascular invasion (LVI), necrosis, progesterone receptor (PR) status, and the presence of triple negative disease. Tumors with LVI and necrosis had more positive PRL-3 expression compared to tumors without LVI or necrosis (P = 0.05 and 0.03, respectively). Triple negative and cerb-B overexpressed breast cancers were found to be more positive PRL-3 expression than hormone receptor positive with cerb-B negative groups (luminal A) (P = 0.02).We could not find any relationship between PRL-3 expression and overall survival (OS) or disease-free survival (DFS) (P > 0.05). CONCLUSION: Although PRL-3 expression was related to LVI or necrosis which is important for tumor invasiveness, we could not find that PRL-3 as an important prognostic factor in breast cancer patients. In addition, triple negative and cerb-B overexpressed tumors, which had worse prognosis compared to hormone receptor positive without cerb-B expressed group, associated with also PRL-3 positivity more than PRL-3 negative group.

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    • "Numerous correlative studies in tumors of the colon, stomach, breast, pancreas and ovaries have shown that PRL-3 expression increases with tumor progression (reviewed in [2], [35]). Further, PRL-3 expression also correlates with tumor clinicopathology and disease outcome in a variety of tumor types [36]–[40]. These correlative studies are supported by numerous functional studies (reviewed in [1], [3]). "
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    ABSTRACT: The metastasis-associated tyrosine phosphatase PRL-3/PTP4A is upregulated in numerous cancers, but the mechanisms modulating PRL-3 activity other than its expression levels have not been investigated. Here we report evidence for both Src-dependent tyrosine phosphorylation of PRL-3 and Src-mediated regulation of PRL-3 biological activities. We used structural mutants, pharmacological inhibitors and siRNA to demonstrate Src-dependent phosphorylation of endogenous PRL-3 in SW480 colon cancer cells. We also demonstrated that PRL-3 was not tyrosine phosphorylated in SYF mouse embryo fibroblasts deficient in Src, Yes and Fyn unless Src was re-expressed. Further, we show that platelet-derived growth factor (PDGF) can stimulate PRL-3 phosphorylation in a Src-dependent manner. Finally, we show that PRL-3-induced cell motility, Matrigel invasion and activation of the cytoskeleton-regulating small GTPase RhoC were abrogated in the presence of the phosphodeficient PRL-3 mutant Y53F, or by use of a Src inhibitor. Thus, PRL-3 requires the activity of a Src kinase, likely Src itself, to promote these cancer-associated phenotypes. Our data establish a model for the regulation of PRL-3 by Src that supports the possibility of their coordinate roles in signaling pathways promoting invasion and metastasis, and supports simultaneous use of novel molecularly targeted therapeutics directed at these proteins.
    PLoS ONE 05/2013; 8(5):e64309. DOI:10.1371/journal.pone.0064309 · 3.23 Impact Factor
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    ABSTRACT: BACKGROUND Internal tandem duplication of FMS-like tyrosine kinase (FLT3-ITD) is well known to be involved in acute myeloid leukemia (AML) progression, but FLT3-ITD–negative AML cases account for 70% to 80% of AML, and the mechanisms underlying their pathology remain unclear. This study identifies protein tyrosine phophatase PRL-3 as a key mediator of FLT3-ITD–negative AML.METHODSA total of 112 FLT3-ITD–negative AML patients were sampled between 2010 and 2013, and the occurrence of PRL-3 hyperexpression in FLT3-ITD–negative AML was evaluated by multivariate probit regression analysis. Overexpression or depletion of endogenous PRL-3 expression with the specific small interfering RNAs was performed to investigate the role of PRL-3 in AML progression. Xenograft models were also used to confirm the oncogenic role of PRL-3.RESULTSCompared to healthy donors, PRL-3 is upregulated more than 3-fold in 40.2% of FLT3-ITD–negative AML patients. PRL-3 expression level is adversely correlated to the overall survival of the AML patients, and the AML relapses accompany with re-upregulation of PRL-3. Mechanistically, aberrant PRL-3 expression promoted cell cycle progression and enhanced the antiapoptotic machinery of AML cells to drug cytotoxicity through downregulation of p21 and upregulation of Cyclin D1 and CDK2 and activation of STAT5 and AKT. Depletion of endogenous PRL-3 sensitizes AML cells to therapeutic drugs, concomitant with apoptosis by upregulation of cleaved PARP (poly ADP ribose polymerase) and apoptosis-related caspases. Xenograft assays further confirmed PRL-3's oncogenic role in leukemogenesis.CONCLUSIONS Our results demonstrated that PRL-3 is a novel independent crucial player in both FLT3-ITD–positive and FLT3-ITD–negative AML and could be a potential therapeutic target. Cancer 2014;000:000-000. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
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