Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival

Abstract

Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and women diagnosed with TNBC currently lack targeted treatment options. To identify novel targets for TNBC, we evaluated phosphatase expression in breast tumors and characterized their contributions to in vitro and in vivo growth of TNBC. Using Affymetrix microarray analysis of 102 breast cancers, we identified 146 phosphatases that were significantly differentially expressed in TNBC compared to estrogen receptor (ER)-positive tumors. Of these, 19 phosphatases were upregulated (0.66-fold; FDR=0.05) in TNBC compared to ER-positive breast cancers. We knocked down 17 overexpressed phosphatases in four triple-negative and four ER-positive breast cancer lines using specific small interfering RNAs and found that depletion of six of these phosphatases significantly reduced growth and anchorage-independent growth of TNBC cells to a greater extent than ER-positive cell lines. Further analysis of the phosphatase PTP4A3 (also known as PRL-3) demonstrated its requirement for G1/S cell cycle progression in all breast cancer cells, but PTP4A3 regulated apoptosis selectively in TNBC cells. In addition, PTP4A3 inhibition reduced the growth of TNBC tumors in vivo. Moreover, in silico analysis revealed the PTP4A3 gene to be amplified in 29% of basal-like breast cancers, and high expression of PTP4A3 could serve as an independent prognostic indicator for worse overall survival. Collectively, these studies define the importance of phosphatase overexpression in TNBC, and lay the foundation for the development of new targeted therapies directed against phosphatases or their respective signaling pathways for TNBC patients.

PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion

“…While another group has preliminarily reported the in vivo effects of knocking down PRL-3 on primary TNBC tumor growth [41], studies examining the effects of PRL-3 knock down or AMPI-109 treatment on invasive and metastatic endpoints in TNBC animal models are urgently needed. Our laboratory is currently pursuing these studies.…”

Molecular Pathways: Targeting Protein Tyrosine Phosphatases in Cancer

“…In addition, analysis of publicly available breast cancer datasets revealed that PTP4A3 expression is significantly elevated in TNBC samples, and in silico analysis revealed that increased PTP4A3 expression is due to gene amplification in 29% of basal like breast cancers. Depletion of PTP4A3 reduced TNBC tumor growth in vivo by reducing proliferation marker (Ki67), phospho-ERK1/2 and p38 levels, while increasing apoptotic markers (1). Highly elevated PTP4A3 expression is also associated with enhanced tumor formation and metastasis by reducing tumor initiating cells in colon cancer mouse models (46).…”

“…den Hollander et al (2016), explored the expression levels of PTPs in 102 human breast cancer samples to identify PTPs that are differentially overexpressed in triple-negative breast cancer (TNBC). In this study, 146 PTPs were differentially expressed in TNBC as compared to estrogen receptor-positive (ER-positive) breast cancer samples.…”

“…Dysregulation of this balance in human cancers is due to the hyper-activation of protein kinases or loss of protein tyrosine phosphatases, which dephosphorylate oncogenic protein kinases. Our recent study was the first report to extensively profile the expression of protein tyrosine phosphatases (PTPs) altered in human breast cancer samples (1). In this review, we will discuss tumor suppressor and oncogenic PTPs in cancer and discuss the current status of PTP inhibitors for cancer therapy.…”

Regulatory mechanisms of phosphatase of regenerating liver (PRL)-3

“…Elegant studies described the amplification of the PRL-3 gene ( PTP4A3 ) in the chromosomal region 8q24.3 in colon cancer metastases [4], breast [21], and gastric carcinomas [22]. Gene amplification is a mechanism to enhance gene expression of oncogenes and could explain PRL-3 overexpression in some human cancer types [4].…”