Up-regulation of α_Vβ₃ integrin expression is a novel molecular response to chemotherapy-induced breast cancer cell damage in an Heregulin (HRG)-dependent manner

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α_vβ₃ integrin has a dual role in angiogenesis; whereas ligated α_vβ₃ activates cell survival pathways and suppresses proapoptotic signals, unligated α_vβ₃ integrin, or integrins bound to soluble ligands actively promote apoptosis. Here, we assessed the role of unligated α_vβ₃ in chemosensitivity of breast cancer cells expressing graded levels of the growth factor heregulin (HRG). Cell surface expression of the RGD-binding integrins α_vβ₃ and α_vβ₅ was measured by flow cytometry in HRG-overexpressing MDA-MB-231 breast cancer cells (MDA-MB-231/WT, MDA-MB-231/VEC) and low-HRG expressing derivatives (MDA-MB-231/AS31) treated with the microtubules-interacting agents (MIAs) paclitaxel and vincristine. Interestingly, quantitative flow cytometric analysis showed that following treatment with MIAs, α_vβ₃ levels were more drastically increased in the MDA-MB-231/AS31 clone (up to 20.8 and 14.5 times, respectively) than in the control MDA MB 231/VEC cells (up to 3.2 and 5 times, respectively). Remarkably, there was no effect of MIAs on the expression of α_vβ₅ integrin. Furthermore, the increase of α_vβ₃ expression was correlated with a dramatic decrease in the viability, alterations in the cell cycle progression and induction of apoptosis in MDA-MB-231 cells following treatment with antitubulin agents. Moreover, a paclitaxel-induced increase of α_vβ₃ expression was observed in MCF-7 cells (MCF-7/WT) and not in an HRG-overexpressing/Adriamicyn-resistant derivative (MCF-7/ADR) which shows cross-resistance to paclitaxel, as observed by cell viability and cell cycle distribution analysis. These findings provide further evidence that the extent of α_vβ₃ up-regulation is dependent on the HRG-expression status of the breast cancer cells. In conclusion, we show that overexpression of α_vβ₃ integrin is related to chemotherapy-induced cell death in low-HRG expressing breast cancer cells. Collectively, these results indicate that α_vβ₃ integrin is drastically overexpressed in low HRG-expressing breast cancer models which are highly sensitive to treatment with microtubule-targeting drugs, thus providing a novel molecular marker of chemosensitivity influenced by the levels of HRG in breast cancer cells.