βIII-Tubulin Regulates Breast Cancer Metastases to the Brain.
βIII-Tubulin Regulates Breast Cancer Metastases to the Brain.
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DOI：
10.1158/1535-7163.mct-14-0950
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发表时间：
2015-05
影响因子：
5.7
通讯作者：
Ahmed AU
中科院分区：
文献类型：
--
作者：
Kanojia D;Morshed RA;Zhang L;Miska JM;Qiao J;Kim JW;Pytel P;Balyasnikova IV;Lesniak MS;Ahmed AU
约10-30%的乳腺癌患者发生脑转移，最终导致预后不良。因此，了解脑转移过程的分子机制以确定相关靶点是至关重要的。我们假设乳腺癌细胞必须表达与大脑相关的标志物，使其能够在大脑微环境中侵袭和存活。我们评估了一组脑主导标志物，发现脑转移性乳腺癌细胞中几种神经元标志物（βIII微管蛋白、巢蛋白和乙酰胆碱酯酶）升高。在这些神经元优势标志物中，硅分析显示βIII微管蛋白（TUBB3）在乳腺癌脑转移（BCBM）中过表达，其表达与远处转移显著相关。在乳腺癌模型（MDA-Br、GLIM2和MDA-MB-468）中进行了TUBB3敲低研究，发现其侵袭能力显著降低。TUBB3受到抑制的MDA-Br细胞在体外也表现出β3整合素、pFAK和pSrc等关键信号分子的缺失。此外，在脑转移性乳腺癌细胞系中，TUBB3敲低降低了其体内转移能力，并显著提高了脑转移模型的存活率。这些结果暗示了TUBB3在赋予乳腺癌细胞脑转移潜能方面的关键作用。
Brain metastases occur in about 10–30% of breast cancer patients, which culminates in a poor prognosis. It is therefore critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII tubulin, Nestin and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2 and MDA-MB-468) which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells.