Up-regulation of αVβ3 integrin expression is a novel molecular response to chemotherapy-induced cell damage in a heregulin-dependent manner

αvβ3 integrin has a dual role in apoptosis. Whereas ligated αvβ3 activates cell survival pathways and suppresses pro-apoptotic signals, unligated αvβ3 or integrins bound to soluble ligands promote apoptosis. In this study, we assessed the role of αvβ3 in chemosensitivity of breast cancer cells expressing different levels of heregulin (HRG). Expression levels of the RGD-binding integrins αvβ3 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 αvβ3 levels were significantly increased in MDA-MB-231 cells. Interestingly, αvβ3 expression was more significantly up-regulated in the MDA-MB-231/AS31 cells than in the parental cells. This MIA-induced increase of αvβ3 expression was correlated with a decrease in cell viability and an increase in apoptosis in MDA-MB-231/AS31 cells, indicating that overexpression of αvβ3 is linked to chemotherapy-induced cell death in low HRG-expressing breast cancer models. Moreover, a paclitaxel-induced increase of αvβ3 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 αvβ3 up-regulation is related to cell damage. These results indicate that αvβ3 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.