Despite great advances in therapy for breast cancer, more than half of patients still face tumor recurrence and drug resistance. Therefore, a better understanding of tumor progression and drug resistance is needed for developing next-generation therapies. Here, we report the role of galactosyltransferase β3GalT5, a key enzyme responsible for the biosynthesis of SSEA3 which is then converted to SSEA4 and Globo-H. We demonstrated that knockdown of β3GalT5 would destruct the complex formation of SSEA3/SSEA4/Globo-H with FAK/CAV1/AKT/RIP and cause the dissociation of RIP from the complex to interact with FADD, thus triggering cancer cell apoptosis and suppressing metastasis. These findings provide a strategy of therapeutics for breast cancer as demonstrated by the combination use of antibodies against Globo-H and SSEA4.

Abstract: The globo-series glycosphingolipids (GSLs) SSEA3, SSEA4, and Globo-H specifically expressed on cancer cells are found to correlate with tumor progression and metastasis, but the functional roles of these GSLs and the key enzyme β1,3-galactosyltransferase V (β3GalT5) that converts Gb4 to SSEA3 remain largely unclear. Here we show that the expression of β3GalT5 significantly correlates with tumor progression and poor survival in patients, and the globo-series GSLs in breast cancer cells form a complex in membrane lipid raft with caveolin-1 (CAV1) and focal adhesion kinase (FAK) which then interact with AKT and receptor-interacting protein kinase (RIP), respectively. Knockdown of β3GalT5 disrupts the complex and induces apoptosis through dissociation of RIP from the complex to interact with the Fas death domain (FADD) and trigger the Fas-dependent pathway. This finding provides a link between SSEA3/SSEA4/Globo-H and the FAK/CAV1/AKT/RIP complex in tumor progression and apoptosis and suggests a direction for the treatment of breast cancer, as demonstrated by the combined use of antibodies against Globo-H and SSEA4.