Polypeptide N-acetylgalactosaminyltransferase 6 disrupts mammary acinar morphogenesis through O-glycosylation of fibronectin.

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.