Protein Marker-Dependent Drug Discovery Targeting Breast Cancer Stem Cells
Abstract
1. Introduction
1.1. Breast Cancer Subtypes and BCSC
1.2. Cancer Stem Cells
2. Current Drug Discovery Strategies That Employ Protein Markers of Breast Cancer Stem Cells
2.1. CD44+/CD24− Are Classic Markers of BCSCs, but What Are They Exactly?
2.2. CD133, Also Known as Prominin-1, Is a Transmembrane Glycoprotein Commonly Used as a Stem Cell Marker Due to Its Role in Suppressing Differentiation
2.3. EpCAM Is a Transmembrane Glycoprotein Expressed in Most Epithelial Cells, and It Mediates Cell–Cell Adhesion Independent of Ca2+, Which Is Unique and Different from Typical Epithelial Cadherins
2.4. CXCR1, or C–X–C Motif Chemokine Receptor 1, Is One of the Receptors for Interleukin-8
2.5. DCLK1
2.6. ALDH1
2.7. ABC Efflux Factors
3. Current Strategies for Targeting Common BCSC Marker Molecules
3.1. Small Molecule Inhibitors
3.2. Drug Delivery
3.3. Immunotherapy
3.4. DCLK1
3.5. ALDH1
3.6. ABC Efflux Factors
4. BCSC Targets in Signaling Pathways
5. Challenges of the Existing Marker-Dependent Drug Discoveries Against Breast Cancer Stem Cells
6. Future Directions in Targeting Breast Cancer Stem Cells
6.1. Circadian Therapy
6.2. CTCs vs. CSCs
6.3. Infradian Rhythms and Therapy
6.4. Artificial Intelligence and Computer-Aided Drug Design
7. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Marker | Description | Role in BCSCs | References |
---|---|---|---|
CD44 | Cell-surface glycoprotein involved in cell adhesion and migration. EMT requires an isoform switch from CD44v to CD44s. | High CD44+/Low CD24− phenotype marks BCSCs; linked to tumorigenicity and metastasis. | [4,18] |
CD24 | Surface protein containing sialic acid sugars that is involved in adhesion and co-stimulatory signaling to immune cells (like CD4+ T cells). | High CD44+/Low CD24− indicates BCSCs with enhanced invasive capabilities, as opposed to the ALDH1+ BCSCs. | [4,18] |
ALDH1 (endogenous marker) | Enzyme catalyzing oxidation of aldehydes and other important physiologic and toxicological functions. | High ALDH1 activity identifies BCSCs, especially the proliferative epithelial subtype associated with increased self-renewal and drug resistance. | [4,20] |
CD133 | Transmembrane glycoprotein associated with stemness as it suppresses differentiation, though its precise mechanism is unclear. | Marker for BCSCs with tumor-initiating capacity; overall, it has been associated with poor survival and prognosis. | [28] |
EpCAM | An adhesion molecule located on the basolateral membrane of cells. | Helps BCSCs with invasion and metastasis, marker for isolating circulating tumor cells (CTCs) enriched with BCSC properties. | [4] |
CXCR1 | Chemokine receptor facilitating migration and invasion via the IL-8 axis. | Regulates BCSC activity; targeted by Reparixin in trials to reduce BCSC populations. | [26,29] |
HER2 | Receptor tyrosine kinase promoting cell growth and differentiation, and its downstream signaling pathway participates in crosstalk with other signaling pathways. | Overexpressed in HER2+ BCSCs; correlates with aggressive tumors by interacting with signaling pathways and increasing stemness features. | [4,30] |
DCLK1 | A CSC marker that is overexpressed in many types of cancer, including breast cancer | Overexpression of DCLK1 in tumor cells will likely contribute to stemness and self-renewal. | [31] |
ABC Efflux Factors | CSCs express a high proportion of ABC transporters | The basis of a flow cytometry method to identify CSC | [32] |
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Huang, A.V.; Kong, Y.; Wang, K.; Brown, M.L.; Mu, D. Protein Marker-Dependent Drug Discovery Targeting Breast Cancer Stem Cells. Int. J. Mol. Sci. 2025, 26, 7935. https://doi.org/10.3390/ijms26167935
Huang AV, Kong Y, Wang K, Brown ML, Mu D. Protein Marker-Dependent Drug Discovery Targeting Breast Cancer Stem Cells. International Journal of Molecular Sciences. 2025; 26(16):7935. https://doi.org/10.3390/ijms26167935
Chicago/Turabian StyleHuang, Ashley V., Yali Kong, Kan Wang, Milton L. Brown, and David Mu. 2025. "Protein Marker-Dependent Drug Discovery Targeting Breast Cancer Stem Cells" International Journal of Molecular Sciences 26, no. 16: 7935. https://doi.org/10.3390/ijms26167935
APA StyleHuang, A. V., Kong, Y., Wang, K., Brown, M. L., & Mu, D. (2025). Protein Marker-Dependent Drug Discovery Targeting Breast Cancer Stem Cells. International Journal of Molecular Sciences, 26(16), 7935. https://doi.org/10.3390/ijms26167935