Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Neoplasia. 2011 Apr;13(4):320-6. doi: 10.1593/neo.101440.
A high expression of short and immature O-glycans is one of the prominent features of breast cancer cells, which would be attributed to the upregulated expression of glycosyltransferases. Therefore, a detailed elucidation of glycosyltransferases and their substrate(s) may improve our understandings for their roles in mammary carcinogenesis. Here we report that overexpression of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6), a glycosyltransferase involved in the initial step of O-glycosylation, has transformational potentials through disruptive acinar morphogenesis and cellular changes similar to epithelial-to-mesenchymal transition in normal mammary epithelial cell, MCF10A. As one of the critical O-glycan substrates, we identified fibronectin that was O-glycosylated in vivo and thereby stabilized by GALNT6. Because knockdown of fibronectin abrogated the disruptive proliferation caused by introduction of GALNT6 into epithelial cells, our findings suggest that GALNT6-fibronectin pathway should be a critical component for breast cancer development and progression.
短链和不成熟 O-聚糖的高表达是乳腺癌细胞的显著特征之一，这归因于糖基转移酶的上调表达。因此，详细阐明糖基转移酶及其底物可能会增进我们对它们在乳腺发生中的作用的理解。在这里，我们报告了参与 O-糖基化初始步骤的多肽 N-乙酰半乳糖胺基转移酶 6（GALNT6）的过表达具有转化潜能，可通过破坏腺泡形态发生和细胞变化类似于正常乳腺上皮细胞 MCF10A 中的上皮间质转化。作为关键的 O-聚糖底物之一，我们鉴定了纤维连接蛋白，它在体内发生 O-糖基化，并因此被 GALNT6 稳定。由于纤维连接蛋白的敲低消除了引入上皮细胞的 GALNT6 引起的破坏性增殖，我们的发现表明 GALNT6-纤维连接蛋白途径应该是乳腺癌发展和进展的关键组成部分。
