{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T05:36:00Z","timestamp":1764308160404,"version":"3.46.0"},"reference-count":44,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"MEXT\/JSPS KAKENHI","doi-asserted-by":"publisher","award":["16K08660"],"award-info":[{"award-number":["16K08660"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015638","name":"Japanese Breast Cancer Society","doi-asserted-by":"crossref","award":["24"],"award-info":[{"award-number":["24"]}],"id":[{"id":"10.13039\/100015638","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Research Promotion Grant","award":["25-01 to NH"],"award-info":[{"award-number":["25-01 to NH"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In triple-negative breast cancer (TNBC), the clinicopathological significance of the expression of a second estrogen receptor, ER\u03b2, remains unclear. Further, although the clinicopathological significance of mutant p53 and androgen receptor (AR) has been investigated in TNBC, they have not been established as therapeutic targets. Experimental studies reported the importance of cross-talk between ER\u03b2 and p53 or AR in TNBC. In this study, we immunohistochemically examined ER\u03b2 expression in surgical specimens of TNBC obtained from postmenopausal patients who underwent surgery without neoadjuvant therapy and investigated the relationship between ER\u03b2 expression and various clinicopathological factors, including clinical outcome, while also considering p53 and AR. No significant difference in clinical outcome was noted according to the ER\u03b2 status alone (p = 0.2908). However, the ER\u03b2 status did affect the relationship between the clinical outcome and p53 or AR status; p53-positive or AR-positive group exhibited significantly more favorable clinical outcomes than p53-negative or AR-negative group, respectively, in the ER\u03b2-positive group (p53, p = 0.0265; AR, p = 0.0285), but not in the ER\u03b2-negative group (p53, p = 0.7228; AR, p = 0.7734). This may be the result of a functional interaction between ER\u03b2 and p53 or AR. The role of ER\u03b2 in TNBC will be elucidated in further complex studies considering multiple molecules.<\/jats:p>","DOI":"10.3390\/ijms262311459","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T15:56:41Z","timestamp":1764172601000},"page":"11459","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of ER\u03b2 in Triple-Negative Breast Cancer Associated with p53 and Androgen Receptor"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7967-3563","authenticated-orcid":false,"given":"Kei","family":"Ito","sequence":"first","affiliation":[{"name":"Department of Pathology, Toho University Faculty of Medicine, Omori-Nishi 5-21-16, Ota-ku, Tokyo 143-8540, Japan"},{"name":"Department of Medical Technology, Faculty of Health Sciences, Tsukuba International University, Manabe 6-20-1, Tsuchiura 300-0051, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoko","family":"Honma","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology, Toho University Faculty of Medicine, Omori-Nishi 5-21-16, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideaki","family":"Ogata","sequence":"additional","affiliation":[{"name":"Department of Breast and Endocrine Surgery, Toho University Omori Medical Center, Omori-Nishi 6-11-1, Ota-ku, Tokyo 143-8541, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akimitsu","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama 236-0004, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika","family":"Miyashita","sequence":"additional","affiliation":[{"name":"Palliative Care Nursing, Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Shogoin-Kawahara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomio","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Sakaecho 35-2, Itabashi-ku, Tokyo 173-0015, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6385-8341","authenticated-orcid":false,"given":"Eiichi","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Kanokoden 1-1, Chikusa-ku, Nagoya 464-8681, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazutoshi","family":"Shibuya","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology, Toho University Faculty of Medicine, Omori-Nishi 5-21-16, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetuo","family":"Mikami","sequence":"additional","affiliation":[{"name":"Department of Pathology, Toho University Faculty of Medicine, Omori-Nishi 5-21-16, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masataka","family":"Sawaki","sequence":"additional","affiliation":[{"name":"Department of Breast Oncology, Nagoya Medical Center, National Hospital Organization 4-1-1 Sannomaru, Naka-ku, Nagoya 460-0001, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1016\/S0140-6736(16)32454-0","article-title":"Molecular Alterations in Triple-Negative Breast Cancer-the Road to New Treatment Strategies","volume":"389","author":"Denkert","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3885","DOI":"10.1021\/acs.jmedchem.3c02232","article-title":"Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315","volume":"67","author":"Fu","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Treeck, O., Sch\u00fcler-Toprak, S., and Ortmann, O. (2020). Estrogen Actions in Triple-Negative Breast Cancer. Cells, 9.","DOI":"10.3390\/cells9112358"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1097\/00000478-200312000-00002","article-title":"Declining Estrogen Receptor-beta Expression Defines Malignant Progression of Human Breast Neoplasia","volume":"27","author":"Shaaban","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Grober, O.M.V., Mutarelli, M., Giurato, G., Ravo, M., Cicatiello, L., De Filippo, M.R., Ferraro, L., Nassa, G., Papa, M.F., and Paris, O. (2011). Global Analysis of Estrogen Receptor Beta Binding to Breast Cancer Cell Genome Reveals an Extensive Interplay with Estrogen Receptor Alpha for Target Gene Regulation. BMC Genom., 12.","DOI":"10.1186\/1471-2164-12-36"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s10549-007-9749-7","article-title":"Effects of Exon-Deleted Estrogen Receptor \u0392 Transcript Variants on Growth, Apoptosis and Gene Expression of Human Breast Cancer Cell Lines","volume":"110","author":"Treeck","year":"2007","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1186\/s13046-019-1359-9","article-title":"Estrogen Receptor \u0392 Inhibits Breast Cancer Cells Migration and Invasion through CLDN6-Mediated Autophagy","volume":"38","author":"Song","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1146\/annurev.physiol.70.113006.100518","article-title":"Estrogen Signaling through the Transmembrane G Protein\u2013Coupled Receptor GPR30","volume":"70","author":"Prossnitz","year":"2008","journal-title":"Annu. Rev. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1038\/onc.2015.353","article-title":"Estrogen Promotes the Brain Metastatic Colonization of Triple Negative Breast Cancer Cells Via an Astrocyte-Mediated Paracrine Mechanism","volume":"35","author":"Sartorius","year":"2016","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sch\u00fcler-Toprak, S., H\u00e4ring, J., Inwald, E.C., Moehle, C., Ortmann, O., and Treeck, O. (2016). Agonists and Knockdown of Estrogen Receptor \u0392 Differentially Affect Invasion of Triple-Negative Breast Cancer Cells in Vitro. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2973-y"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"878","DOI":"10.3892\/ijo.2014.2778","article-title":"Estrogen Receptor \u0392 Selective Agonists Reduce Invasiveness of Triple-Negative Breast Cancer Cells","volume":"46","author":"Hinsche","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1093\/jnci\/djz051","article-title":"TP53 Status as a Determinant of Pro- vs Anti-Tumorigenic Effects of Estrogen Receptor-Beta in Breast Cancer","volume":"111","author":"Mukhopadhyay","year":"2019","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Honma, N., Matsuda, Y., and Mikami, T. (2021). Carcinogenesis of Triple-Negative Breast Cancer and Sex Steroid Hormones. Cancers, 13.","DOI":"10.3390\/cancers13112588"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bhattarai, S., Klimov, S., Mittal, K., Krishnamurti, U., Li, X., Oprea-Ilies, G., Wetherilt, C., Riaz, A., Aleskandarany, M.A., and Green, A.R. (2019). Prognostic Role of Androgen Receptor in Triple Negative Breast Cancer: A Multi-Institutional Study. Cancers, 11.","DOI":"10.3390\/cancers11070995"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gasparini, P., Fassan, M., Cascione, L., Guler, G., Balci, S., Irkkan, C., Paisie, C., Lovat, F., Morrison, C., and Zhang, J. (2014). Androgen Receptor Status is a Prognostic Marker in Non-Basal Triple Negative Breast Cancers and Determines Novel Therapeutic Options. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088525"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1245\/s10434-014-3984-z","article-title":"Androgen Receptor Expression Predicts Decreased Survival in Early Stage Triple-Negative Breast Cancer","volume":"22","author":"Choi","year":"2014","journal-title":"Ann. Surg. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1007\/s13193-024-01877-2","article-title":"Incidence and Prognostic Significance of Androgen Receptors (AR) in Indian Triple-Negative Breast Cancer (TNBC)","volume":"15","author":"Mishra","year":"2024","journal-title":"Indian J. Surg. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.humpath.2021.01.005","article-title":"Clinicopathological Characteristics and Prognostic Marker of Triple-Negative Breast Cancer in Older Women","volume":"111","author":"Honma","year":"2021","journal-title":"Hum. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"56364","DOI":"10.18632\/oncotarget.16913","article-title":"Androgen Receptor Expression Identifies Patient with Favorable Outcome in Operable Triple Negative Breast Cancer","volume":"8","author":"Hu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1200\/JCO.2007.14.2968","article-title":"Clinical Importance of Estrogen Receptor-\u0392 Evaluation in Breast Cancer Patients Treated with Adjuvant Tamoxifen Therapy","volume":"26","author":"Honma","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s10549-015-3467-3","article-title":"ER\u03b21 Inversely Correlates with PTEN\/PI3K\/AKT Pathway and Predicts a Favorable Prognosis in Triple-Negative Breast Cancer","volume":"152","author":"Wang","year":"2015","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s10549-014-3050-3","article-title":"ER\u03b2 Splice Variant Expression in Four Large Cohorts of Human Breast Cancer Patient Tumors","volume":"146","author":"Wimberly","year":"2020","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_23","first-page":"1246","article-title":"Prognostic Significance of Full-Length Estrogen Receptor Beta Expression in Stage I-III Triple Negative Breast Cancer","volume":"5","author":"Shanle","year":"2015","journal-title":"Am. J. Transl. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1111\/pin.13429","article-title":"Clinicopathological Importance of Bcl-2 and p53 in Postmenopausal Triple-negative Breast Carcinoma and Association with Age","volume":"74","author":"Ito","year":"2024","journal-title":"Pathol. Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1093\/jnci\/85.3.200","article-title":"Association of p53 Protein Expression with Tumor Cell Proliferation Rate and Clinical Outcome in Node-Negative Breast Cancer","volume":"85","author":"Allred","year":"1993","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1038\/nature07986","article-title":"Cytoplasmic Functions of the Tumour Suppressor p53","volume":"458","author":"Green","year":"2009","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s41419-021-03463-8","article-title":"p53 Induces ARTS to Promote Mitochondrial Apoptosis","volume":"12","author":"Hao","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.breast.2013.07.005","article-title":"P53 in Breast Cancer Subtypes and New Insights into Response to Chemotherapy","volume":"22","author":"Bertheau","year":"2013","journal-title":"Breast"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13599","DOI":"10.18632\/oncotarget.7300","article-title":"ER\u03b2 Decreases the Invasiveness of Triple-Negative Breast Cancer Cells by Regulating Mutant p53 Oncogenic Function","volume":"7","author":"Bado","year":"2016","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.3390\/cancers14051120","article-title":"Estrogen Receptor-Beta2 (ER\u03b22)\u2013Mutant p53\u2013FOXM1 Axis: A Novel Driver of Proliferation, Chemoresistance, and Disease Progression in High Grade Serous Ovarian Cancer (HGSOC)","volume":"14","author":"Oturkar","year":"2022","journal-title":"Cancers"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1093\/oncolo\/oyac281","article-title":"Therapeutic Role of Tamoxifen for Triple-Negative Breast Cancer: Leveraging the Interaction between ER\u03b2 and Mutant p53","volume":"28","author":"Scarpetti","year":"2023","journal-title":"Oncologist"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s13046-017-0545-x","article-title":"ER\u03b21 Inhibits Metastasis of Androgen Receptor-Positive Triple-Negative Breast Cancer by Suppressing ZEB1","volume":"36","author":"Song","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1007\/s00432-019-02872-9","article-title":"Estrogen Receptor Beta Increases Sensitivity to Enzalutamide in Androgen Receptor-Positive Triple-Negative Breast Cancer","volume":"145","author":"Anestis","year":"2019","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.1210\/endo.139.10.6216","article-title":"Interaction of Estrogenic Chemicals and Phytoestrogens with Estrogen Receptor Beta","volume":"139","author":"Kuiper","year":"1998","journal-title":"Endocrinology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1158\/0008-5472.CAN-03-2446","article-title":"Estrogen Receptor Beta Inhibits Human Breast Cancer Cell Proliferation and Tumor Formation by Causing a G2 Cell Cycle Arrest","volume":"64","author":"Paruthiyil","year":"2004","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1158\/1078-0432.CCR-13-2943","article-title":"TP53 Mutation Spectrum in Breast Cancer is Subtype Specific and has Distinct Prognostic Relevance","volume":"20","author":"Vollan","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1210\/me.2012-1107","article-title":"Minireview: The Androgen Receptor in Breast Tissues: Growth Inhibitor, Tumor Suppressor, Oncogene?","volume":"26","author":"Hickey","year":"2012","journal-title":"Mol. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ravaioli, S., Maltoni, R., Pasculli, B., Parrella, P., Giudetti, A.M., Vergara, D., Tumedei, M.M., Pirini, F., and Bravaccini, S. (2022). Androgen Receptor in Breast Cancer: The \u201c5W\u201d Questions. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.977331"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3994","DOI":"10.1038\/sj.onc.1209415","article-title":"An Estrogen Receptor-Negative Breast Cancer Subset Characterized by a Hormonally Regulated Transcriptional Program and Response to Androgen","volume":"25","author":"Doane","year":"2006","journal-title":"Oncogene"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"R21","DOI":"10.1186\/bcr3619","article-title":"Estrogen Receptor Beta as a Novel Target of Androgen Receptor Action in Breast Cancer Cell Lines","volume":"16","author":"Rizza","year":"2014","journal-title":"Breast Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Crespo, B., Illera, J.C., Silvan, G., Lopez-Plaza, P., Herrera De La Muela, M., De La Puente Yag\u00fce, M., Diaz Del Arco, C., Illera, M.J., and Caceres, S. (2024). Androgen and Estrogen \u0392 Receptor Expression Enhances Efficacy of Antihormonal Treatments in Triple-Negative Breast Cancer Cell Lines. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031471"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1093\/hmg\/ddt077","article-title":"Androgen Receptor-Induced Tumor Suppressor, KLLN, Inhibits Breast Cancer Growth and Transcriptionally Activates p53\/p73-Mediated Apoptosis in Breast Carcinomas","volume":"22","author":"Wang","year":"2013","journal-title":"Human Mol. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Honma, N., Saji, S., Mikami, T., Yoshimura, N., Mori, S., Saito, Y., Murayama, S., and Harada, N. (2017). Estrogen-Related Factors in the Frontal Lobe of Alzheimer\u2019s Disease Patients and Importance of Body Mass Index. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-00815-3"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1046\/j.1365-2559.2003.01542.x","article-title":"Breast Carcinoma in Women over the Age of 85: Distinct Histological Pattern and Androgen, Oestrogen, and Progesterone Receptor Status","volume":"42","author":"Honma","year":"2003","journal-title":"Histopathology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11459\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T05:32:34Z","timestamp":1764307954000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11459"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":44,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311459"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311459","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,11,26]]}}}