Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2012;7(7):e39432. doi: 10.1371/journal.pone.0039432. Epub 2012 Jul 9.
Rab31 is a member of the Ras superfamily of small GTPases that has been linked to poor outcomes in patients with breast cancer. The MUC1-C oncoprotein is aberrantly overexpressed in most human breast cancers and also confers a poor prognosis. The present results demonstrate that MUC1-C induces Rab31 expression in estrogen receptor positive (ER+) breast cancer cells. We show that MUC1-C forms a complex with estrogen receptor α (ERα) on the Rab31 promoter and activates Rab31 gene transcription in an estrogen-dependent manner. In turn, Rab31 contributes to the upregulation of MUC1-C abundance in breast cancer cells by attenuating degradation of MUC1-C in lysosomes. Expression of an inactive Rab31(S20N) mutant in nonmalignant breast epithelial cells confirmed that Rab31 regulates MUC1-C expression. The functional significance of the MUC1-C/Rab31 interaction is supported by the demonstration that Rab31 confers the formation of mammospheres by a MUC1-C-dependent mechanism. Analysis of microarray databases further showed that (i) Rab31 is expressed at higher levels in breast cancers as compared to that in normal breast tissues, (ii) MUC1+ and ER+ breast cancers have increased levels of Rab31 expression, and (iii) patients with Rab31-positive breast tumors have a significantly decreased ten-year overall survival as compared to those with Rab31-negative tumors. These findings indicate that MUC1-C and Rab31 function in an autoinductive loop that contributes to overexpression of MUC1-C in breast cancer cells.
Rab31 是 Ras 超家族的小 GTPase 成员，与乳腺癌患者的不良预后有关。MUC1-C 癌蛋白在大多数人类乳腺癌中异常过表达，并且也预示着不良的预后。本研究结果表明，MUC1-C 在雌激素受体阳性（ER+）乳腺癌细胞中诱导 Rab31 表达。我们表明，MUC1-C 在 Rab31 启动子上与雌激素受体 α（ERα）形成复合物，并以雌激素依赖的方式激活 Rab31 基因转录。反过来，Rab31 通过减弱溶酶体中 MUC1-C 的降解，有助于上调乳腺癌细胞中 MUC1-C 的丰度。在非恶性乳腺上皮细胞中表达失活的 Rab31（S20N）突变证实了 Rab31 通过调节 MUC1-C 的表达。MUC1-C/Rab31 相互作用的功能意义得到了证实，即 Rab31 通过 MUC1-C 依赖的机制赋予形成乳腺球体的能力。对微阵列数据库的进一步分析表明：（i）与正常乳腺组织相比，Rab31 在乳腺癌中表达水平更高；（ii）MUC1+和 ER+乳腺癌中 Rab31 表达水平增加；（iii）Rab31 阳性乳腺癌患者的十年总生存率明显低于 Rab31 阴性肿瘤患者。这些发现表明，MUC1-C 和 Rab31 以自诱导环的形式发挥作用，有助于乳腺癌细胞中 MUC1-C 的过度表达。
