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Volume 26
Issue 23
10.3390/ijms262311599
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Review

Emerging Breast Cancer Subpopulations: Functional Heterogeneity Beyond the Classical Subtypes

by
Amalia Kotsifaki
1,
Georgia Kalouda
1,
Efthymios Karalexis
1,
Martha Stathaki
2,
Georgios Metaxas
2 and
Athanasios Armakolas
1,*
1
Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
2
Department of Surgery, Elena Venizelou Hospital, 11521 Athens, Greece
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(23), 11599; https://doi.org/10.3390/ijms262311599 (registering DOI)
Submission received: 29 September 2025 / Revised: 19 November 2025 / Accepted: 28 November 2025 / Published: 29 November 2025
(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)
Review Reports Versions Notes

Abstract

Breast cancer (BC) is increasingly recognized as a heterogeneous disease, with complexity that extends beyond the classical luminal A/B, HER2-enriched, and triple-negative framework. Advances in molecular and functional profiling have uncovered emerging subpopulations, including HER2-low, claudin-low, BRCA-deficient (“ BRCAness”), and refined TNBC subsets, such as luminal AR (LAR) and basal-like immune variants, that extend beyond traditional taxonomies. These novel classifications provide additional resolutions, offering both prognostic insight and therapeutic opportunities. In this comprehensive review, we integrate evidence from genomic, epigenetic, proteomic, immune-related, and liquid biopsy biomarkers, underscoring how they define the biology of these subgroups and predict responses to targeted therapies, such as antibody–drug conjugates, PARP inhibitors, and immune checkpoint blockade. We further highlight the role of the tumor microenvironment (TME) and intratumoral heterogeneity in shaping these entities. Collectively, recognition of emerging subtypes as clinically actionable groups represents a paradigm shift from static receptor-based models to dynamic, biomarker-driven frameworks that refine prognosis, enable patient stratification, and support precision oncology in aggressive BC.
Keywords: breast cancer subtypes; emerging populations; functional heterogeneity; HER2-low; claudin-low; BRCAness; prognostic biomarkers; tumor microenvironment; precision oncology; intratumoral heterogeneity breast cancer subtypes; emerging populations; functional heterogeneity; HER2-low; claudin-low; BRCAness; prognostic biomarkers; tumor microenvironment; precision oncology; intratumoral heterogeneity

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MDPI and ACS Style

Kotsifaki, A.; Kalouda, G.; Karalexis, E.; Stathaki, M.; Metaxas, G.; Armakolas, A. Emerging Breast Cancer Subpopulations: Functional Heterogeneity Beyond the Classical Subtypes. Int. J. Mol. Sci. 2025, 26, 11599. https://doi.org/10.3390/ijms262311599

AMA Style

Kotsifaki A, Kalouda G, Karalexis E, Stathaki M, Metaxas G, Armakolas A. Emerging Breast Cancer Subpopulations: Functional Heterogeneity Beyond the Classical Subtypes. International Journal of Molecular Sciences. 2025; 26(23):11599. https://doi.org/10.3390/ijms262311599

Chicago/Turabian Style

Kotsifaki, Amalia, Georgia Kalouda, Efthymios Karalexis, Martha Stathaki, Georgios Metaxas, and Athanasios Armakolas. 2025. "Emerging Breast Cancer Subpopulations: Functional Heterogeneity Beyond the Classical Subtypes" International Journal of Molecular Sciences 26, no. 23: 11599. https://doi.org/10.3390/ijms262311599

APA Style

Kotsifaki, A., Kalouda, G., Karalexis, E., Stathaki, M., Metaxas, G., & Armakolas, A. (2025). Emerging Breast Cancer Subpopulations: Functional Heterogeneity Beyond the Classical Subtypes. International Journal of Molecular Sciences, 26(23), 11599. https://doi.org/10.3390/ijms262311599

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