Up-regulation of α Vβ 3 integrin expression is a novel molecular response to chemotherapy-induced cell damage in a heregulin-dependent manner

Abstract

α vβ 3 integrin has a dual role in apoptosis. Whereas ligated α vβ 3 activates cell survival pathways and suppresses pro-apoptotic signals, unligated α vβ 3 or integrins bound to soluble ligands promote apoptosis. In this study, we assessed the role of α vβ 3 in chemosensitivity of breast cancer cells expressing different levels of heregulin (HRG). Expression levels of the RGD-binding integrins α vβ 3 were measured in MDA-MB-231 human breast cancer cells and its low HRG-expressing derivative (MDA-MB-231/AS31) treated with the microtubule-interfering agents (MIAs) paclitaxel and vincristine. Following treatment, only α vβ 3 levels were significantly increased in MDA-MB-231 cells. Interestingly, α vβ 3 expression was more significantly up-regulated in the MDA-MB-231/AS31 cells than in the parental cells. This MIA-induced increase of α vβ 3 expression was correlated with a decrease in cell viability and an increase in apoptosis in MDA-MB-231/AS31 cells, indicating that overexpression of α vβ 3 is linked to chemotherapy-induced cell death in low HRG-expressing breast cancer models. Moreover, a paclitaxel-induced increase of α vβ 3 was also observed in MCF-7 cells but not in an doxorubicin-resistant derivative that shows cross-resistance to paclitaxel, further providing evidence that the extent of α vβ 3 up-regulation is related to cell damage. These results indicate that α vβ 3 integrin is dramatically up-regulated in low HRG-expressing breast cancer models that are highly responsive to MIAs, thus providing a novel molecular marker of chemosensitivity influenced by HRG levels in breast cancer cells.