Abstract
hMena and the epithelial specific isoform hMena11a are actin cytoskeleton regulatory proteins belonging to the Ena/VASP family. EGF treatment of breast cancer cell lines upregulates hMena/hMena11a expression and phosphorylates hMena11a, suggesting cross-talk between the ErbB receptor family and hMena/hMena11a in breast cancer. The aim of this study was to determine whether the hMena/hMena11a overexpression cooperates with HER-2 signalling, thereby affecting the HER2 mitogenic activity in breast cancer. In a cohort of breast cancer tissue samples a significant correlation among hMena, HER2 overexpression, the proliferation index (high Ki67), and phosphorylated MAPK and AKT was found and among the molecular subtypes the highest frequency of hMena overexpressing tumors was found in the HER2 subtype. From a clinical viewpoint, concomitant overexpression of HER2 and hMena identifies a subgroup of breast cancer patients showing the worst prognosis, indicating that hMena overexpression adds prognostic information to HER2 overexpressing tumors. To identify a functional link between HER2 and hMena, we show here that HER2 transfection in MCF7 cells increased hMena/hMena11a expression and hMena11a phosphorylation. On the other hand, hMena/hMena11a knock-down reduced HER3, AKT and p44/42 MAPK phosphorylation and inhibited the EGF and NRG1-dependent HER2 phosphorylation and cell proliferation. Of functional significance, hMena/hMena11a knock-down reduced the mitogenic activity of EGF and NRG1. Collectively these data provide new insights into the relevance of hMena and hMena11a as downstream effectors of the ErbB receptor family which may represent a novel prognostic indicator in breast cancer progression, helping to stratify patients.
Highlights
Breast cancer is a heterogeneous disease and in recent years the introduction of new targeted therapeutic approaches highlights the need to stratify patients and to identify accurate biomarkers to select the best therapeutic choice
HER2 overexpression and activity affect hMena/hMena11a overexpression in human breast cancer cell lines We previously reported that epithelial cancer cell lines express hMena and the epithelial specific hMena11a isoform [16]
Treatment for 24 h of MCF7-HER2 with respect to control (MCF7)-pcDNA3 and SKBr3 cells respectively with NRG1 (10 ng/ml) and EGF (100 ng/ml), factors that indirectly activate HER2 by heterodimerization with HER3 and EGFR respectively, determined an increase in hMena RNA (1.8 and 2.1 fold respectively) (Figure 3 panel C). These results show that the growth factor-mediated hMena protein upregulation reported previously [15,16] is related to an increase in hMena mRNA and indicate that HER2 overexpression and activity contribute to hMena/hMena11a overexpression in breast cancer (BC) cell lines
Summary
Breast cancer is a heterogeneous disease and in recent years the introduction of new targeted therapeutic approaches highlights the need to stratify patients and to identify accurate biomarkers to select the best therapeutic choice. The molecular classification of breast tumors has identified tumor subtypes, among which the overexpression of the ErbB family of receptors is confined to tumors with unfavourable prognosis [1]. The human ErbB receptor family comprises four tyrosine kinases members (EGFR, HER2, HER3 and HER4) and their deregulation has been correlated with cancer development and progression [1,2]. Upon ligand binding ErbB receptors undergo homodimerization or heterodimerization and activate a complex signalling network that controls tumor cell proliferation as well as motility through different pathways that regulate rearrangements of the actin cytoskeleton [3]. The two main signalling pathways downstream from the ErbB receptors are the phosphatidylinositol 39-kinase (PI3K) and the mitogen activated protein kinase (MAPK) [4]. MAPK activation is responsible for the EGF dependent mitogenic effect in normal and transformed mammary epithelia [9] and its role in cell cycle progression is sustained by cytoskeletal organization [10]
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