Vellon Luciano, Menendez Javier A, Liu Hong, Lupu Ruth
Department of Medicine, Breast Cancer Translational Research Laboratory, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL, USA.
Differentiation. 2007 Nov;75(9):819-30. doi: 10.1111/j.1432-0436.2007.00241.x.
alpha(v)beta(3) integrin has a dual role in apoptosis. Whereas ligated alpha(v)beta(3) activates cell survival pathways and suppresses pro-apoptotic signals, unligated alpha(v)beta(3) or integrins bound to soluble ligands promote apoptosis. In this study, we assessed the role of alpha(v)beta(3) in chemosensitivity of breast cancer cells expressing different levels of heregulin (HRG). Expression levels of the RGD-binding integrins alpha(v)beta(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 alpha(v)beta(3) levels were significantly increased in MDA-MB-231 cells. Interestingly, alpha(v)beta(3) expression was more significantly up-regulated in the MDA-MB-231/AS31 cells than in the parental cells. This MIA-induced increase of alpha(v)beta(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 alpha(v)beta(3) is linked to chemotherapy-induced cell death in low HRG-expressing breast cancer models. Moreover, a paclitaxel-induced increase of alpha(v)beta(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 alpha(v)beta(3) up-regulation is related to cell damage. These results indicate that alpha(v)beta(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.
α(v)β(3)整合素在细胞凋亡中具有双重作用。与配体结合的α(v)β(3)激活细胞存活途径并抑制促凋亡信号，而未与配体结合的α(v)β(3)或与可溶性配体结合的整合素则促进细胞凋亡。在本研究中，我们评估了α(v)β(3)在表达不同水平的人表皮生长因子（HRG）的乳腺癌细胞化学敏感性中的作用。在用微管干扰剂（MIAs）紫杉醇和长春新碱处理的MDA-MB-231人乳腺癌细胞及其低HRG表达衍生物（MDA-MB-231/AS31）中，测量了RGD结合整合素α(v)β(3)的表达水平。处理后，仅MDA-MB-231细胞中的α(v)β(3)水平显著增加。有趣的是，MDA-MB-231/AS31细胞中α(v)β(3)的表达上调比亲本细胞更显著。这种MIAs诱导的α(v)β(3)表达增加与MDA-MB-231/AS31细胞的细胞活力降低和凋亡增加相关，表明α(v)β(3)的过表达与低HRG表达乳腺癌模型中化疗诱导的细胞死亡有关。此外，在MCF-7细胞中也观察到紫杉醇诱导的α(v)β(3)增加，但在对紫杉醇显示交叉耐药性的阿霉素耐药衍生物中未观察到，这进一步证明α(v)β(3)上调的程度与细胞损伤有关。这些结果表明，在对MIAs高度敏感的低HRG表达乳腺癌模型中，α(v)β(3)整合素显著上调，从而为受乳腺癌细胞中HRG水平影响的化学敏感性提供了一种新的分子标记。
