PEA-15 Inhibits Tumor Cell Invasion by Binding to Extracellular Signal-Regulated Kinase 1/2

Abstract

Phosphoprotein enriched in astrocytes of 15 kDa (PEA-15) binds to extracellular signal-regulated kinase 1 and 2 (ERK1/2) mitogen-activated protein (MAP) kinases to alter ERK1/2 cellular localization and target preferences and binds to adaptors in the extrinsic cell death pathway to block apoptosis. Here, we report that PEA-15 protein expression is inversely correlated with the invasive behavior of breast cancer in an immunohistochemical analysis of a breast cancer progression tissue microarray. Short hairpin RNA-mediated inhibition of PEA-15 expression increased the invasion of PEA-15-expressing tumor cells in vitro, suggesting a causative role for PEA-15 in the inhibition of invasion. This causative role was confirmed by the finding that the enforced expression of PEA-15 in invasive tumor cells reduced invasion. The effect of PEA-15 on tumor invasion is mediated by its interaction with ERK1/2 as shown by the following: (a) PEA-15 mutants that fail to bind ERK1/2 did not inhibit invasion; (b) overexpression of ERK1 or activated MAP/ERK kinase (MEK) reversed the inhibitory effect of PEA-15; (c) when an inhibitor of ERK1/2 activation reduced invasion, PEA-15 expression did not significantly reduce invasion further. Furthermore, we find that the effect of PEA-15 on invasion seems to relate to the nuclear localization of activated ERK1/2. PEA-15 inhibits invasion by keeping ERK out of the nucleus, as a PEA-15 mutant that cannot prevent ERK nuclear localization was not able to inhibit invasion. In addition, membrane-localized ERK1, which sequesters endogenous ERK1 to prevent its nuclear localization, also inhibited invasion. These results reveal that PEA-15 regulates cancer cell invasion via its ability to bind ERK1/2 and indicate that nuclear entry of ERK1/2 is important in tumor behavior. [Cancer Res 2007;67(4):1536-44]

Association of the Breast Cancer Antiestrogen Resistance Protein 1 (BCAR1) and BCAR3 Scaffolding Proteins in Cell Signaling and Antiestrogen Resistance

“…The inhibitory effects of PEA15 on the growth of breast cancer cells and its ability to counteract the antiestrogen resistance of MCF7 cells overexpressing BCAR3 together with previous data showing a correlation of high PEA15 expression with benign markers and low invasiveness in clinical breast cancer specimens (54,56) suggest that tumors with high PEA15 levels are less malignant than tumors with low PEA15. Thus, PEA15 protein expression should be considered when evaluating the prognostic significance of BCAR1 and BCAR3 in breast cancer specimens (4, 5, 14, 18, 19).…”

“…Previous studies reported that PEA15 inhibits breast cancer cell growth and invasiveness concomitant with sequestration of cytoplasmic ERK1/2 but did not demonstrate the importance of ERK1/2 binding in the growth effects of PEA15, a protein capable of multiple activities (54,56,67). Interestingly, high PEA15 protein expression in breast cancer clinical samples has been significantly correlated with positive estrogen/progesterone receptor status and a low level of the proliferation marker, proliferating cell nuclear antigen (54).…”

High ERK Protein Expression Levels Correlate with Shorter Survival in Triple-Negative Breast Cancer Patients

“…In breast cancer patients, low PEA-15 expression was previously linked with aggressive forms of the disease. Similarly, greater PEA-15 expression was associated with less invasion in breast cancer through effects on the ERK pathway [17]. We also found that PEA-15 expression levels were lower in high-grade than in low-grade breast tumors.…”

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

“…[91] The same strategy is utilized for the induction of apoptosis, by the pro-apoptotic protein Bik, in lung epithelial cells [92] and by the death-associated…”

“…As mentioned before, sequestering ERKs at the cytoplasm, whereby ERKs nuclear signals are impeded, is sufficient for abrogating growth and/ or potentiating apoptosis. [91][92][93] Recently, a nuclear translocation signal: Ser-Pro-Ser, has been identified within ERKs ''insert.'' These serines are phosphorylated upon stimulation, promoting ERKs translocation to the nucleus.…”