Genus Oncology, Boston, MA, USA.
Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Oncogene. 2014 Jun 26;33(26):3422-31. doi: 10.1038/onc.2013.308. Epub 2013 Aug 5.
Patients with HER2-positive breast cancer often exhibit intrinsic or acquired resistance to trastuzumab treatment. The transmembrane mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in breast cancer cells and associates with HER2. The present studies demonstrate that silencing MUC1 C-terminal subunit (MUC1-C) in HER2-overexpressing SKBR3 and BT474 breast cancer cells results in the downregulation of constitutive HER2 activation. Moreover, treatment with the MUC1-C inhibitor, GO-203, was associated with disruption of MUC1-C/HER2 complexes and decreases in tyrosine-phosphorylated HER2 (p-HER2) levels. In studies of trastuzumab-resistant SKBR3R and BT474R cells, we found that the association between MUC1-C and HER2 is markedly increased (∼20-fold) as compared with that in sensitive cells. In addition, silencing MUC1-C in the trastuzumab-resistant cells or treatment with GO-203 decreased p-HER2 and AKT activation. Moreover, targeting MUC1-C was associated with the downregulation of phospho-p27 and cyclin E, which confer trastuzumab resistance. Consistent with these results, targeting MUC1-C inhibited the growth and clonogenic survival of both trastuzumab-resistant cells. Our results further demonstrate that silencing MUC1-C reverses resistance to trastuzumab and that the combination of GO-203 and trastuzumab is highly synergistic. These findings indicate that MUC1-C contributes to constitutive activation of the HER2 pathway and that targeting MUC1-C represents a potential approach to abrogate trastuzumab resistance.
患有 HER2 阳性乳腺癌的患者通常对曲妥珠单抗治疗表现出内在或获得性耐药。跨膜粘蛋白 1（MUC1）癌蛋白在乳腺癌细胞中异常过表达，并与 HER2 相关。本研究表明，沉默过表达 HER2 的 SKBR3 和 BT474 乳腺癌细胞中的 MUC1 C 端亚基（MUC1-C）可导致组成型 HER2 激活下调。此外，用 MUC1-C 抑制剂 GO-203 处理与 MUC1-C/HER2 复合物的破坏和酪氨酸磷酸化 HER2（p-HER2）水平降低有关。在曲妥珠单抗耐药 SKBR3R 和 BT474R 细胞的研究中，我们发现与敏感细胞相比，MUC1-C 与 HER2 的关联显着增加（约 20 倍）。此外，沉默耐药细胞中的 MUC1-C 或用 GO-203 处理可降低 p-HER2 和 AKT 激活。此外，靶向 MUC1-C 与下调磷酸化 p27 和细胞周期蛋白 E 有关，后者赋予曲妥珠单抗耐药性。与这些结果一致，靶向 MUC1-C 抑制了两种曲妥珠单抗耐药细胞的生长和集落形成存活。我们的研究结果进一步表明，沉默 MUC1-C 可逆转曲妥珠单抗耐药性，并且 GO-203 和曲妥珠单抗的组合具有高度协同作用。这些发现表明 MUC1-C 有助于 HER2 通路的组成型激活，并且靶向 MUC1-C 代表了一种消除曲妥珠单抗耐药性的潜在方法。
