Mismatch Repair Protein Expression Patterns in HER 2 Positive Breast Cancer Patients: A Clinical Pathological Correlation

Christeen Hanna; Mayada I. Yalda

doi:10.31632/ijalsr.2026.v09i03.015

Christeen Hanna Department of Medical Lab Technology, College of Health and Medical Technology -Shekhan/ Duhok Polytechnic University, Duhok 1006, Kurdistan Region, Iraq https://orcid.org/0009-0008-9475-8774
Mayada I. Yalda Pathology Department, College of Medicine, University of Duhok, Kurdistan Region, Iraq https://orcid.org/0000-0003-2778-9147

DOI https://doi.org/10.31632/ijalsr.2026.v09i03.015

Abstract

Background: Mismatch repair (MMR) deficiency is linked to tumor genomic instability in diverse cancers. Although MMR loss has been comprehensively analyzed for the therapeutic responses in multiple malignancies, the capacity of MMR loss to impact disease severity in breast cancer (BC) and prognostic factors, including human epidermal growth factor receptor 2 (HER2) positive subtypes is still to be clarified. Aim: The aim of this study was to analyze the expression of MMR proteins (MLH1, PMS2, MSH2, and MSH6) in HER2-positive BC, as well as to check their association with ER/PR, Ki67, and tumor grade. Furthermore, researchers explored if the expression of MMR genes may reflect patient heterogeneity and contribute to developing resistance to therapy in hormone receptor-positive breast cancer subtypes. Methods: In this study, 63 HER2+ BC specimens, collected from 2016 to 2024, were analyzed for MMR protein expression (MLH1, PMS2, MSH2 and MSH6) via immunohistochemistry (IHC). Fluorescence in situ hybridization (FISH) was used to confirm HER2 amplification in cases of HER2 two-pluses in IHC analysis. Results were correlated with clinicopathological data, including estrogen receptor (ER), progesterone receptor (PR), Ki67 and tumor grade among others. Statistical significance was set at p < 0.05. Results: All HER2-positive breast cancer specimens demonstrated positive MMR protein expression with varying intensities. ER-positive cases exhibited a higher frequency of strong MMR expressions compared to ER-negative cases, which showed a higher proportion of weak PMS2 expression (43.2% vs. 21.1%, respectively). Most HER2-positive breast cancer patients (81%) showed Ki67 expression greater than 15%, predominantly observed in high-grade tumors. However, weak MMR expression showed no significant correlation with Ki67 or hormone receptor status. Conclusion: The total intact MMR with intensity alterations, especially for PMS2 in ER+ tumors, may reflect tumor heterogeneity and could contribute to therapy resistance in hormone receptor-positive BC. The young age at presentation, particularly for ER+ cases and the high value of Ki67 with the intact MMR may imply a broader, possibly genetic or molecular basis that should be addressed. MMR profiling has clinical relevance and can help take precision oncology further in BC management. Recommendation: Future studies should include larger cohorts and molecular analyses to clarify the role of MMR alterations in HER2-positive breast cancer. Incorporating MMR testing into routine diagnostics may improve treatment planning, and further research is needed to assess its impact on therapy response and patient outcomes.

Keywords: Breast Cancer, HER2, Hormonal Receptors, Immunohistochemistry, Mismatch Repair Deficiency

Downloads

Download data is not yet available.

References

Ali, G. S., Yaqo, R. T., & Abdullah, M. A. (2024). Clinicopathological Implications of Mismatch Repair Status in Endometrioid Endometrial Cancer in Duhok City. Cureus, 16(3), e56861. https://doi.org/10.7759/cureus.56861
Cheng, A. S., Leung, S. C., Gao, D., Burugu, S., Anurag, M., Ellis, M. J., & Nielsen, T. O. (2020). Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort. Breast Cancer Research and Treatment, 179(1), 3-10. https://doi.org/10.1007/s10549-019-05438-y
Fusco, N., Lopez, G., Corti, C., Pesenti, C., Colapietro, P., Ercoli, G., ... & Bosari, S. (2018). Mismatch repair protein loss as a prognostic and predictive biomarker in breast cancers regardless of microsatellite instability. JNCI Cancer Spectrum, 2(4), pky056. https://doi.org/10.1093/jncics/pky056
Grizzi, G., Ghidini, M., Botticelli, A., Tomasello, G., Ghidini, A., Grossi, F., ... & Petrelli, F. (2020). Strategies for increasing the effectiveness of aromatase inhibitors in locally advanced breast cancer: an evidence-based review on current options. Cancer Management and Research, 675-686. https://doi.org/10.2147/CMAR.S202965
Hacking, S. M., Yakirevich, E., & Wang, Y. (2022). From immunohistochemistry to new digital ecosystems: a state-of-the-art biomarker review for precision breast cancer medicine. Cancers, 14(14), 3469. https://doi.org/10.3390/cancers14143469
He, Y., Zhang, L., Zhou, R., Wang, Y., & Chen, H. (2022). The role of DNA mismatch repair in immunotherapy of human cancer. International Journal of Biological Sciences, 18(7), 2821- 2832. https://doi.org/10.7150/ijbs.71714
Heer, E., Harper, A., Escandor, N., Sung, H., McCormack, V., & Fidler-Benaoudia, M. M. (2020). Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study. The Lancet Global Health, 8(8), e1027-e1037. https://doi.org/10.1016/s2214-109x(20)30215-1
Huang, H., Zhou, J., Chen, H., Li, J., Zhang, C., Jiang, X., & Ni, C. (2021). The immunomodulatory effects of endocrine therapy in breast cancer. Journal of Experimental & Clinical Cancer Research, 40(1), 19. https://doi.org/10.1186/s13046-020-01788-4
Ivanova, M., Venetis, K., Guerini-Rocco, E., Bottiglieri, L., Mastropasqua, M. G., Garrone, O., ... & Ghidini, M. (2022). HER2 in metastatic colorectal cancer: pathology, somatic alterations, and perspectives for novel therapeutic schemes. Life, 12(9), 1403. https://doi.org/10.3390/life12091403
Kiss, A., Nádorvári, M. L., Kulka, J., Barbai, T., Rásó, E., Kenessey, I., ... & Tímár, J. (2024). Overview of a comparative analysis of microsatellite instability and standard mismatch repair protein-deficiency tests in a large cancer cohort. Die Pathologie, 45(Suppl 1), 63-66. https://doi.org/10.1007/s00292-024-01397-4
Klümper, N., Grünwald, V., Hartmann, A., Hölzel, M., & Eckstein, M. (2024). The Role of Microsatellite Instability/DNA Mismatch Repair Deficiency and Tumor Mutational Burden as Biomarkers in Predicting Response to Immunotherapy in Castration-resistant Prostate Cancer. European Urology, S0302-2838. https://doi.org/10.1016/j.eururo.2024.04.026
Lopez, G., Noale, M., Corti, C., Gaudioso, G., Sajjadi, E., Venetis, K., ... & Fusco, N. (2020). PTEN expression as a complementary biomarker for mismatch repair testing in breast cancer. International Journal of Molecular Sciences, 21(4), 1461. https://doi.org/10.3390/ijms21041461
Mohammed, S. S., Al Mahmoodi, H., Yalda, M. I., & Yalda, M. (2024). Expression of Axl Receptor Tyrosine Kinase and Its Association with Ki-67 Proliferation Marker, BCL-2 Anti-apoptotic Protein, Hormone Receptor Status, and HER2/Neu Status in Breast Cancer Among Women from Duhok, Iraq. Cureus, 16(9), e70204. https://doi.org/10.7759/cureus.70204
Pećina-Šlaus, N., Kafka, A., Salamon, I., & Bukovac, A. (2020). Mismatch repair pathway, genome stability and cancer. Frontiers in Molecular Biosciences, 7, 122. https://doi.org/10.3389/fmolb.2020.00122
Piumatti, E., Vitiello, P. P., Amodio, V., Bardelli, A., & Germano, G. (2025). Mismatch repair as a dynamic and clinically actionable vulnerability in cancer. Cancer Research, 85(22), 4299-4314. https://doi.org/10.1158/0008-5472.CAN-25-2255
Sajjadi, E., Venetis, K., Piciotti, R., Invernizzi, M., Guerini-Rocco, E., Haricharan, S., & Fusco, N. (2021). Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization. Cancer Cell International, 21(1), 266. https://doi.org/10.1186/s12935-021-01976-y
Sandilya, U., & K, M. (2024). Expression of Ki-67 in Invasive Breast Carcinoma and Its Correlation with Different Clinicopathological Features. Cureus, 16(9), e69820. https://doi.org/10.7759/cureus.69820
Sepulveda, A. R., Hamilton, S. R., Allegra, C. J., Grody, W., Cushman-Vokoun, A. M., Funkhouser, W. K., ... & Nowak, J. A. (2017). Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. American Journal of Clinical Pathology, 147(3), 221-260. https://doi.org/10.1093/ajcp/aqw209
Siegel, R. L., Miller, K. D., Wagle, N. S., & Jemal, A. (2023). Cancer statistics, 2023. CA: A Cancer Journal for Clinicians, 73(1), 17-48. https://doi.org/10.3322/caac.21763
Valenza, C., Rizzo, G., Passalacqua, M. I., Boldrini, L., Corti, C., Trapani, D., & Curigliano, G. (2023). Evolving treatment landscape of immunotherapy in breast cancer: current issues and future perspectives. Therapeutic Advances in Medical Oncology, 15, 17588359221146129. https://doi.org/10.1177/17588359221146129
Valiente, M., Sepúlveda, J. M., & Pérez, A. (2023). Emerging targets for cancer treatment: S100A9/RAGE. ESMO Open, 8(1), 100751. https://doi.org/10.1016/j.esmoop.2022.100751
Venetis, K., Sajjadi, E., Haricharan, S., & Fusco, N. (2020). Mismatch repair testing in breast cancer: the path to tumor-specific immuno-oncology biomarkers. Translational Cancer Research, 9(7), 4060–4064. https://doi.org/10.21037/tcr-20-1852
Wang, C., Zheng, Z., Wu, C., Zhang, D., Wang, Y., Zhang, S., ... & Zhou, R. (2025). Adipose-Derived Exosomes: mediators of crosstalk between Adipose tissue and cancer. Cancer Biology & Therapy, 26(1), 2547564. https://doi.org/10.1080/15384047.2025.2547564
Wolff, A. C., Somerfield, M. R., Dowsett, M., Hammond, M. E. H., Hayes, D. F., McShane, L. M., ... & Allison, K. H. (2023). Human epidermal growth factor receptor 2 testing in breast cancer: ASCO–College of American Pathologists Guideline Update. Journal of Clinical Oncology, 41(22), 3867-3872. https://doi.org/10.1200/JCO.22.02864
Yalda, M. (2022). The Ten-Year Survival Rate for Breast Cancer Females in Kurdistan/Iraq: Special Facts and Features. HMU Conference Proceedings, (3), 27–37. https://doi.org/10.15218/crewh.2022.03
Yalda, M. I. (2013). Estrogen and progesterone receptors (ER and PR) status of breast cancer cases in Kurdistan and their correlation with pathologic prognostic variables. Medical Journal of Babylon, 10(1), 75-48.