Breast cancer has become one of the most common malignant tumors among women worldwide. Compared with European and American countries, the proportion of late-stage diagnoses among Chinese patients is relatively high. Although the diagnosis and treatment methods for breast cancer are constantly being updated and improved, most patients still face problems such as recurrence, metastasis, and drug resistance due to the heterogeneity of breast cancer itself. Therefore, it is urgent to find new therapeutic targets for breast cancer. B-cell lymphoma 6 protein (BCL6), as a transcriptional repressor, plays an important role in the occurrence and development of breast cancer. Studies have shown that high expression of BCL6 is closely related to the malignant characteristics, metastatic ability, and prognosis of tumors, and inhibiting its expression can enhance the sensitivity of breast cancer cells to chemotherapy drugs. This article reviews the expression and function of BCL6 in breast cancer, related molecular mechanisms, potential therapeutic targets, research progress in chemotherapy resistance, and discusses its future development and application in breast cancer.
References
[1]
Harbeck, N. and Gnant, M. (2017) Breast Cancer. The Lancet, 389, 1134-1150. https://doi.org/10.1016/s0140-6736(16)31891-8
[2]
Louwen, F., Ritter, A., Kreis, N., Hoock, S.C., Solbach, C. and Yuan, J. (2025) B-Cell Lymphoma 6 in Breast Cancer: Molecular Mechanisms and Clinical Significance. Critical Reviews in Biochemistry and Molecular Biology, 60, 80-106. https://doi.org/10.1080/10409238.2025.2521319
[3]
Muschol-Steinmetz, C., Jasmer, B., Kreis, N., Steinhäuser, K., Ritter, A., Rolle, U., et al. (2016) B-Cell Lymphoma 6 Promotes Proliferation and Survival of Trophoblastic Cells. Cell Cycle, 15, 827-839. https://doi.org/10.1080/15384101.2016.1149273
[4]
Sultan, M., Nearing, J.T., Brown, J.M., Huynh, T.T., Cruickshank, B.M., Lamoureaux, E., et al. (2021) An in Vivo Genome-Wide shRNA Screen Identifies BCL6 as a Targetable Biomarker of Paclitaxel Resistance in Breast Cancer. Molecular Oncology, 15, 2046-2064. https://doi.org/10.1002/1878-0261.12964
[5]
Beck, D., Zobel, J., Barber, R., Evans, S., Lezina, L., Allchin, R.L., et al. (2016) Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a Bcl6-Dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-Cell Lymphoma. Journal of Biological Chemistry, 291, 16686-16698. https://doi.org/10.1074/jbc.m116.736868
[6]
Walker, S.R., Nelson, E.A., Yeh, J.E., Pinello, L., Yuan, G. and Frank, D.A. (2013) STAT5 Outcompetes STAT3 to Regulate the Expression of the Oncogenic Transcriptional Modulator Bcl6. Molecular and Cellular Biology, 33, 2879-2890. https://doi.org/10.1128/mcb.01620-12
[7]
Badr, E. (2016) BCL6 mRNA Expression Level in Invasive Duct Carcinoma Not Otherwise Specified. Journal of Clinical and Diagnostic Research, 10, XC01-XC04. https://doi.org/10.7860/jcdr/2016/22796.8985
[8]
Walker, S.R., Liu, S., Xiang, M., Nicolais, M., Hatzi, K., Giannopoulou, E., et al. (2014) The Transcriptional Modulator BCL6 as a Molecular Target for Breast Cancer Therapy. Oncogene, 34, 1073-1082. https://doi.org/10.1038/onc.2014.61
[9]
Ollila, T.A. and Olszewski, A.J. (2018) Extranodal Diffuse Large B Cell Lymphoma: Molecular Features, Prognosis, and Risk of Central Nervous System Recurrence. Current Treatment Options in Oncology, 19, Article No. 38. https://doi.org/10.1007/s11864-018-0555-8
[10]
Luo, H., Yi, P., Wang, W., Li, K., Meng, L., Li, J., et al. (2019) Clinicopathological Features, Treatment, and Prognosis in Primary Diffuse Large B Cell Lymphoma of the Breast: A Retrospective Study of 46 Patients. Medical Science Monitor, 25, 8671-8682. https://doi.org/10.12659/msm.917550
[11]
Riedell, P.A. and Smith, S.M. (2018) Double Hit and Double Expressors in Lymphoma: Definition and Treatment. Cancer, 124, 4622-4632. https://doi.org/10.1002/cncr.31646
[12]
Li, Z., Min, Z., Lin, A., et al. (2017) Expression and Significance of BCL-6 and ZEB2 in Breast Cancer. Journal of Clinical and Experimental Pathology, 33, 50-54.
[13]
Liongue, C., Almohaisen, F.L.J. and Ward, A.C. (2024) B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond. International Journal of Molecular Sciences, 25, Article No. 10968. https://doi.org/10.3390/ijms252010968
[14]
Zhang, W., Han, Q., Ding, Y., Zhou, H., Chen, Z., Wang, J., et al. (2022) BCL6 Drives Stem-Like Memory Macrophages Differentiation to Foster Tumor Progression. Cellular and Molecular Life Sciences, 80, Article No. 14. https://doi.org/10.1007/s00018-022-04660-0
[15]
Wu, Q., Liu, X., Yan, H., He, Y., Ye, S., Cheng, X., et al. (2014) B-Cell Lymphoma 6 Protein Stimulates Oncogenicity of Human Breast Cancer Cells. BMC Cancer, 14, Article No. 418. https://doi.org/10.1186/1471-2407-14-418
[16]
De Santis, F., Romero-Cordoba, S.L., Castagnoli, L., Volpari, T., Faraci, S., Fucà, G., et al. (2022) BCL6 and the Notch Pathway: A Signaling Axis Leading to a Novel Druggable Biotarget in Triple Negative Breast Cancer. Cellular Oncology, 45, 257-274. https://doi.org/10.1007/s13402-022-00663-y
[17]
Fan, Q., Meng, X., Liang, H., Zhang, H., Liu, X., Li, L., et al. (2016) miR-10a Inhibits Cell Proliferation and Promotes Cell Apoptosis by Targeting BCL6 in Diffuse Large B-Cell Lymphoma. Protein & Cell, 7, 899-912. https://doi.org/10.1007/s13238-016-0316-z
[18]
Zhao, D.M., Geng, X.J., Tan, L., et al. (2018) Study on the Expression of IL-6 in the Serum of Patients with Endometriosis and Its Potential Mechanism. Chinese Journal of Immunology, 34, 1707-1711.
[19]
Li, K., Liu, Y., Ding, Y., Zhang, Z., Feng, J., Hu, J., et al. (2022) BCL6 Is Regulated by the MAPK/ELK1 Axis and Promotes Kras-Driven Lung Cancer. Journal of Clinical Investigation, 132, e161308. https://doi.org/10.1172/jci161308
[20]
Hua, H., He, X.Z. and Li, X. (2018) Significance of BCL2 and BCL6 Expression in Ulcerative Colitis. Journal of Rare and Uncommon Diseases, 25, 4-6.
[21]
He, X.Z., Zou, B., Li, X., et al. (2016) Expression and Significance of BCL-2 and BCL-6 in Gastric Cancer Patients. Hainan Medical Journal, 27, 3112-3114.
[22]
Han, R., et al. (2024) BCL6 Participates in Alternative Splicing Regulation in Recurrent Miscarriage in HTR-8 Cells. Chinese Journal of Birth Health & Heredity, 32, 1796-1802.
[23]
Li, Y. and Zhang, X.Y. (2023) Expression of BCL-6, BIM, PUMA, BNIP3 and BNIP3L in Skin Lesions of Patients with Psoriasis and Normal Skin. Journal of Practical Dermatology, 16, 327-330.
[24]
Zhang, Y., Wang, H., Ren, C., Yu, H., Fang, W., Zhang, N., et al. (2019) Correlation between C-MYC, BCL-2, and BCL-6 Protein Expression and Gene Translocation as Biomarkers in Diagnosis and Prognosis of Diffuse Large B-Cell Lymphoma. Frontiers in Pharmacology, 9, Article No. 1497. https://doi.org/10.3389/fphar.2018.01497
[25]
Ding, Y.H., Wu, J.J., Wang, Q., et al. (2018) Homoharringtonine Induces Apoptosis in Chronic Myeloid Leukemia K562 Cells via the mTOR Pathway. Journal of Experimental Hematology, 26, 105-109.
[26]
Wei, M., Xu, L.Y., Han, J., et al. (2018) Effect of Estradiol on Proliferation of Ectopic Endometrial Glandular Epithelial Cells and Expression of BCL6 Protein. Shandong Medical Journal, 58, 13-15.
[27]
Li, S., Niu, X., Xi, Y., Deng, S., Li, C., Zhao, Q., et al. (2013) T Cell Vaccination Inhibits Th1/Th17/Tfh Frequencies and Production of Autoantibodies in Collagen-Induced Arthritis. Clinical and Developmental Immunology, 2013, Article ID: 967301. https://doi.org/10.1155/2013/967301
[28]
He, J., Wu, M., Xiong, L., Gong, Y., Yu, R., Peng, W., et al. (2020) BTB/POZ Zinc Finger Protein ZBTB16 Inhibits Breast Cancer Proliferation and Metastasis through Upregulating ZBTB28 and Antagonizing BCL6/ZBTB27. Clinical Epigenetics, 12, Article No. 82. https://doi.org/10.1186/s13148-020-00867-9
[29]
Wang, Z., Tan, M., Zhang, J., Ren, H. and Ye, X. (2025) BCL6 Inhibitors Exhibit Therapeutic Effects on Breast Cancer Cells through the BCL6-STAT4 Pathway. Anti-Cancer Agents in Medicinal Chemistry, 25, 1447-1455. https://doi.org/10.2174/0118715206364308250410104338
[30]
Cardenas, M.G., Oswald, E., Yu, W., Xue, F., MacKerell, A.D. and Melnick, A.M. (2017) The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target. Clinical Cancer Research, 23, 885-893. https://doi.org/10.1158/1078-0432.ccr-16-2071
[31]
Furth, P.A., Nakles, R.E., Millman, S., Diaz-Cruz, E.S. and Cabrera, M.C. (2011) Signal Transducer and Activator of Transcription 5 as a Key Signaling Pathway in Normal Mammary Gland Developmental Biology and Breast Cancer. Breast Cancer Research, 13, Article No. 220. https://doi.org/10.1186/bcr2921
[32]
Tran, T.H., Utama, F.E., Lin, J., Yang, N., Sjolund, A.B., Ryder, A., et al. (2010) Prolactin Inhibits BCL6 Expression in Breast Cancer through a Stat5a-Dependent Mechanism. Cancer Research, 70, 1711-1721. https://doi.org/10.1158/0008-5472.can-09-2314
[33]
Song, D., Cui, M., Zhao, G., et al. (2014) Pathway-Based Analysis of Breast Cancer. American Journal of Translational Research, 6, 302-311.
[34]
Tamma, R., Ruggieri, S., Annese, T., Simone, G., Mangia, A., Rega, S., et al. (2018) BCL6/p53 Expression, Macrophages/Mast Cells Infiltration and Microvascular Density in Invasive Breast Carcinoma. Oncotarget, 9, 22727-22740. https://doi.org/10.18632/oncotarget.25220
[35]
Tang, H.M., Ding, W., Ding, Y.H., et al. (2019) Regulation of BCL6 Protein Expression Level by Ubiquitination Modification in K562/G01 Cells and Its Effect on Cell Proliferation and Apoptosis. Journal of Experimental Hematology, 27, 379-384.
[36]
Sun, X.M., Mei, W., He, B., et al. (2023) Expression and Prognostic Significance of Ki-67, BCL-6, BCL-2 and TEFM in Diffuse Large B-Cell Lymphoma. Journal of Dali University, 8, 62-69.
[37]
Li, S. and Yang, J.Y. (2017) Relationship between Methylation in the Promoter Region of BCL6B Gene and Colon Cancer. Chinese Journal of Clinical Research, 30, 729-731.
[38]
Kargbo, R.B. (2025) Targeted Degradation of BCL6 Using Novel Bifunctional Degraders: A New Therapeutic Strategy for BCL6-Positive Cancers. ACS Medicinal Chemistry Letters, 16, 740-742. https://doi.org/10.1021/acsmedchemlett.5c00181
[39]
Kim, M.H., Kim, G.M., Ahn, J.M., Ryu, W., Kim, S., Kim, J.H., et al. (2023) Copy Number Aberrations in Circulating Tumor DNA Enables Prognosis Prediction and Molecular Characterization of Breast Cancer. JNCI: Journal of the National Cancer Institute, 115, 1036-1049. https://doi.org/10.1093/jnci/djad080
[40]
Li, L., Pan, Z.J., Zhang, H.Q., et al. (2020) Expression and Significance of Ki-67 and BCL-6 Genes in Non-Hodgkin’s Lymphoma Tissues, Hydroquinone-Mutated TK6 Lymphoblasts and Their Nude Mouse Xenograft Tissues. Chinese Journal of Cancer Prevention and Treatment, 27, 1064-1069.
[41]
Gu, Y., Li, A.F., Zhao, J.L., et al. (2018) BCL6B Inhibits Proliferation and Migration of Colorectal Cancer Cell HCT116 and Its Possible Mechanism. Journal of Chongqing Medical University, 43, 36-41.
[42]
Hoang, T.H., Zhao, Y., Lam, Y., Piekos, S., Han, Y., Reilly, C., et al. (2019) BioTarget: A Computational Framework Identifying Cancer Type Specific Transcriptional Targets of Immune Response Pathways. Scientific Reports, 9, Article No. 9029. https://doi.org/10.1038/s41598-019-45304-x
[43]
Wei, Z., Gao, W., Wu, Y., Ni, B. and Tian, Y. (2015) Mutual Interaction between BCL6 and miRNAs Contributing to the Pathogenesis of Various Cancers. Clinical and Translational Oncology, 17, 841-846. https://doi.org/10.1007/s12094-015-1322-y
