Department of Pathophysiology in Basic Science, Medical College of Xiamen University, Xiamen, Fujian, China.
PLoS One. 2012;7(10):e48178. doi: 10.1371/journal.pone.0048178. Epub 2012 Oct 25.
Twist2 (Dermo1) has been shown to mediate the epithelial-mesenchymal transition (EMT) to promote tumor invasion and even metastasis. However, the involvement of EMT in breast cancer progression is highly debated, partially due to clinical observations showing that the majority of human breast carcinoma metastases express E-cadherin and maintain their epithelial morphology. The molecular mechanism by which Twist2 participates in EMT of breast cancer in vivo remains poorly understood.
We examined Twist2 expression pattern in human breast carcinomas by western blot and tissue microarray, and analyzed Twist2 cellular localization by confocal microscopy, cell fractionation and other approaches.
Twist2 expression was significantly increased in breast cancer. Cytoplasmic Twist2 positive cancer cells expressing E-cadherin on the cellular membrane were mainly located at tumor center of primary carcinomas and lymph metastases, while cancer cells with nuclear Twist2 clearly showed loss of E-cadherin and were detected at the invasive front in ductal breast carcinomas. In addition, ectopically stable-expressed Twist2 was found to localize in the cytoplasm of cancer cells. Collectively, these data indicate that upregulation of cytoplasmic Twist2 is correlated with tumor histological type and tumor metastasis in human breast cancers.
The differential cellular distribution of Twist2 may be associated with tumor progression. The cytoplasmic Twist2 in cancer cells at tumor center of primary carcinomas and lymph metastases contributes to the maintenance of epithelial cancer characteristics expressing E-cadherin in a noninvasive state, while the nuclear Twist2 at the cancer invasion front activates EMT to deprive epithelial property of neoplastic cells, thus facilitating invasion and metastasis. These findings suggest that heterogeneous expression of Twist2 in tumors may have a functional link to tumor progression.
Twist2（Dermo1）已被证明能介导上皮间质转化（EMT），从而促进肿瘤侵袭，甚至转移。然而，EMT 在乳腺癌进展中的作用仍存在争议，部分原因是临床观察表明，大多数人类乳腺癌转移瘤表达 E-钙黏蛋白并保持上皮形态。Twist2 参与体内乳腺癌 EMT 的分子机制仍知之甚少。
我们通过 Western blot 和组织微阵列检测 Twist2 在人类乳腺癌中的表达模式，并通过共聚焦显微镜、细胞分级分离和其他方法分析 Twist2 的细胞定位。
Twist2 在乳腺癌中表达明显增加。细胞质中表达 E-钙黏蛋白的 Twist2 阳性癌细胞主要位于原发性乳腺癌和淋巴结转移的肿瘤中心，而核内 Twist2 阳性的癌细胞则明显失去 E-钙黏蛋白，并在乳腺导管癌的侵袭前沿检测到。此外，稳定过表达的 Twist2 被发现定位于癌细胞的细胞质中。综上所述，这些数据表明细胞质中 Twist2 的上调与人类乳腺癌的肿瘤组织学类型和肿瘤转移有关。
Twist2 的细胞分布差异可能与肿瘤进展有关。原发性乳腺癌和淋巴结转移瘤肿瘤中心的癌细胞中的细胞质 Twist2 有助于维持表达 E-钙黏蛋白的上皮癌特征，处于非侵袭状态，而癌细胞侵袭前沿的核内 Twist2 激活 EMT，剥夺肿瘤细胞的上皮特性，从而促进侵袭和转移。这些发现表明肿瘤中 Twist2 的异质性表达可能与肿瘤进展有功能联系。
