Abstract 3140: High ERK protein expression levels correlate with shorter survival in triple-negative breast cancer

Abstract

Abstract ERK, a member of the MAPK pathway, plays an important role in cell proliferation and differentiation and facilitates cell migration through its effects on cell-matrix contacts. ERK1 and ERK2 are dually phosphorylated by MEK on threonine and tyrosine residues. PEA-15, a novel 15-kDa serine-phosphorylated protein, acts as a master regulator of ERK by regulating ERK's cellular localization. Specifically, PEA-15 can sequester ERK in the cytoplasm, thereby preventing its activation. We have previously shown that PEA-15 blocks the activity of ERK by inhibiting the transcription factor Elk-1 and that high levels of PEA-15 protein expression in women with ovarian cancer were independently associated with prolonged overall survival. ERK is the convergence point for a number of upstream signaling pathways, meaning that multiple pathways could be blocked by inhibition of ERK alone. Triple-negative breast cancer (TNBC) is negative for HER2, estrogen receptor, and progesterone receptor and no specific targeted therapy is available to improve patient outcomes. These tumors are resistant to current approved targeted therapies such as hormonal therapy and trastuzumab. The MAPK pathway is activated in TNBCs. Thus, we investigated the overall clinical impact of MAPK/ERK activity in TNBC. To understand the role of ERK in TNBC, we determined the relative quantities of targets of the MAPK/ERK signaling pathway (ERK2, phosphorylated MAPK [pMAPK], MEK1, PEA-15, pPEA-15, TSC2, and p27) in 97 triple-negative human breast tumors by reverse phase protein arrays. To assess the relationship between ERK and PEA-15 or pPEA-15 Pearson correlation coefficients were calculated. We conducted a multivariable analysis with a Cox proportional hazards model to assess the independent predictive value of ERK2 expression along with other prognostic factors in TNBC. The median age for triple negative patients was 55 years (range, 27-86). Most patients had stage II disease (60%), with some stage I (20%) and stage III (19%), and most tumors had a histological type of invasive ductal carcinoma (97%) and a nuclear grade of 3 (84%). We observed positive relationships between ERK2 and PEA-15 (P < 0.0001) and between PEA-15 and pPEA-15 (S116) (P < 0.0001). In a multivariable analysis with a Cox proportional hazards model, we found that women with high-ERK2-expressing tumors were at a higher risk of death than those with low-ERK2-expressing tumors (hazard ratio = 2.76, 95% CI 1.19 - 6.41, P = 0.02). High ERK2 expression was associated with shorter survival in patients with TNBC. Our data demonstrate that ERK may be an important therapeutic target for TNBC. We are planning further immunohistochemical studies since PEA-15 is known to regulate ERK based on cellular localization of ERK. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3140.