S100A14, a Member of the EF-hand Calcium-binding Proteins, Is Overexpressed in Breast Cancer and Acts as a Modulator of HER2 Signaling

Xiang Wang,Aiping Luo,Chengshan Xu,Yiqun Che,Shuguang Zhang,Jidong Gao,Zhihua Liu,Hongyan Chen,Yi Li,Fang Ding

doi:10.1074/jbc.m113.469718

Abstract

HER2 is overexpressed in 20–25% of breast cancers. Overexpression of HER2 is an adverse prognostic factor and correlates with decreased patient survival. HER2 stimulates breast tumorigenesis via a number of intracellular signaling molecules, including PI3K/AKT and MAPK/ERK.S100A14,one member of the S100 protein family, is significantly associated with outcome of breast cancer patients. Here, for the first time, we show that S100A14 and HER2 are coexpressed in invasive breast cancer specimens,andthere is a significant correlation between the expression levels of the two proteins by immunohistochemistry. S100A14 and HER2 are colocalized in plasma membrane of breast cancer tissue cells and breast cancer cell lines BT474 and SK-BR3. We demonstrate that S100A14 binds directly to HER2 by co-immunoprecipitation and pull-down assays. Further study shows that residues 956–1154 of the HER2 intracellular domain and residue 83 of S100A14 are essential for the two proteins binding.Moreover,we observe a decrease of HER2 phosphorylation, downstream signaling, and HER2-stimulated cell proliferation in S100A14-silenced MCF-7, BT474, and SK-BR3 cells. Our findings suggest that S100A14 functions as a modulator of HER2 signaling and provide mechanistic evidence for its role in breast cancer progression.

Highlights

The role of S100A14 in tumorigenesis and the underlying mechanisms have not been fully understood
Kaplan-Meier survival analyses demonstrated that S100A14/HER2 was inversely correlated with metastasis-free survival time (Fig. 1E)
No significant difference was found between the expression of S100A14/HER2 and clinicopathological features, such as lymph node metastasis, prognosis, etc., in the present study

Summary

Background

The role of S100A14 in tumorigenesis and the underlying mechanisms have not been fully understood. S100A14, one member of the S100 protein family, is significantly associated with outcome of breast cancer patients. Our findings suggest that S100A14 functions as a modulator of HER2 signaling and provide mechanistic evidence for its role in breast cancer progression. HER2 (human epidermal growth factor receptor 2), known as Neu, ErbB2, or p185, is a transmembrane protein that is encoded by the ERBB2 gene in humans. The EGFR family is involved in regulating cell proliferation, survival, and differentiation through interlinked signal transduction involving hyperactivation of the PI3K/AKT and MAPK/ ERK pathways [1]. We demonstrate for the first time that there is a strong correlation between S100A14 and HER2 expression in breast cancer tissues, and S100A14 can interact with HER2 by co-immunoprecipitation and pull-down assays. This study provides further insights into the HER2 signaling pathway

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION