Although breast cancer treatment has evolved significantly in recent years, drug resistance remains a major challenge. To identify new targets for breast cancer, we found that stage-specific embryonic antigen 4 (SSEA-4) is expressed in all subtypes of breast cancer cell lines, and the increased expression of the associated enzymes β3GalT5 and ST3Gal2 correlates with poor recurrence-free survival (RFS) in breast cancer. We also found that SSEA-4 antibodies can be rapidly internalized into breast cancer cells, a property that makes SSEA-4 an attractive target for antibody-drug conjugates (ADCs). Furthermore, the SSEA-4 antibody conjugated to the anticancer agents showed efficacy against SSEA-4-positive breast cancer cells, including those resistant to PARP inhibitor, trastuzumab, and CDK7 inhibitor. In addition, SSEA-4 ADCs showed no efficacy in β3GalT5-knockout MDA-MB-231 cells, highlighting the essential role of SSEA-4 as the target antigen for ADCs activity. Our work shows that SSEA-4-ADCs could be a therapeutic option for breast cancers.
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