Antibody-drug conjugates targeting SSEA-4 inhibits growth and migration of SSEA-4 positive breast cancer cells

Muhammad Usama; Yu-Chieh Hsu; Mahdieh Safaei; Chung-Yu Chen; Kyung Ho Han; Yuan-Soon Ho; Hirohito Yamaguchi; Yi-Chuan Li; Mien-Chie Hung; Chi-Huey Wong; Chih-Wei Lin

doi:10.1016/j.canlet.2025.217453

Antibody-drug conjugates targeting SSEA-4 inhibits growth and migration of SSEA-4 positive breast cancer cells

Cancer Lett. 2025 Jan 9:217453. doi: 10.1016/j.canlet.2025.217453. Online ahead of print.

Authors

Affiliations

¹ Institute of Translational Medicine and New Drug Development, China Medical University, Taichung, 406040, Taiwan.
² Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan.
³ Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan.
⁴ Department of Biological Sciences and Biotechnology, Hannam University, 34054 Daejeon, Republic of Korea.
⁵ Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan.
⁶ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Graduate Institute of Cell Biology, China Medical University, Taichung, 406040, Taiwan.
⁷ Department of Biological Science and Technology, China Medical University, Taichung 406040, Taiwan.
⁸ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, 406040, Taiwan; Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung 406040, Taiwan.
⁹ Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
¹⁰ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan.

PMID: 39798832
DOI: 10.1016/j.canlet.2025.217453

Abstract

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.

Keywords: Antibody drug conjugations; Breast Cancer; Drug resistance; SSEA-4 Expression; TNBC.