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

  • Cancer Lett. 2025 Jan 10:611:217453. doi: 10.1016/j.canlet.2025.217453.
Muhammad Usama  1 ,  Yu-Chieh Hsu  2 ,  Mahdieh Safaei  2 ,  Chung-Yu Chen  3 ,  Kyung Ho Han  4 ,  Yuan-Soon Ho  5 ,  Hirohito Yamaguchi  6 ,  Yi-Chuan Li  7 ,  Mien-Chie Hung  8 ,  Chi-Huey Wong  9 ,  Chih-Wei Lin  10
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, USA.
  • 10. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 406040, Taiwan; Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, 406040, Taiwan. Electronic address: [email protected].
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.
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