{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:44:29Z","timestamp":1760060669401,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Hospital Infantil de Mexico, Federico Gomez, the Mexico Federal Funds","award":["HIM\/2017\/114 SSA 1431","HIM\/2012\/012"],"award-info":[{"award-number":["HIM\/2017\/114 SSA 1431","HIM\/2012\/012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Yin Yang 1 (YY1) is a multifunctional transcription factor implicated in gene regulation, cell proliferation, and survival. While its role in breast cancer (BC) has been explored, its prognostic significance remains controversial. In this study, we evaluated nuclear YY1 expression in 276 BC tissue samples using immunohistochemistry (IHC), tissue microarrays (TMAs), and digital pathology (DP). Nuclear staining was quantified using Aperio ImageScope software, focusing on tumor regions to avoid confounding from stromal or non-tumor tissues. This selective and standardized approach enabled precise quantification of YY1 expression. Our results show elevated median YY1 expression in tumor vs. normal matched tissues (p &lt; 0.001). The optimal cutoff for medium-intensity nuclear YY1 expression in tumor areas for overall survival (OS) was established by a receiver operating characteristic (ROC) curve (AUC = 0.718, 95% CI: 0.587\u20130.849, p = 0.008). In contrast, ROC curves showed no prognostic impact (AUC and p-value) for YY1 quantification in whole spots (tumor + normal). As a categorical variable, high YY1 expression was correlated with more aggressive BC features, including tumor size &gt; 3 cm (57.7% vs. 44.2% p = 0.037), the triple-negative breast cancer (TNBC) molecular subtype (27.3% vs. 13.9% p = 0.026), and advanced prognostic stage (III) (31.8% vs. 16.7% p = 0.003), while as a continuous variable, YY1 was associated with higher histological (p = 0.003) and nuclear grades (p = 0.022). High YY1 expression was significantly associated with a reduced OS of BC patients, as shown by Kaplan\u2013Meier curves (HR = 2.227, p = 0.002). Since YY1 was significantly enriched in TNBC, we evaluated its prognostic resolution in this subgroup. But, probably due to the small number of patients within this subset, our results were not statistically significant (HR = 1.317, 95% CI: 0.510\u20133.405, p = 0.566). Next, we performed multivariate Cox regression, confirming YY1 as an independent prognostic factor for overall survival (HR = 1.927, 95% CI: 1.144\u20133.247, p = 0.014). In order to improve prognostic value, we constructed a mathematical model derived from the multivariate Cox regression results, including YYI, AJCC prognostic stage (STA), and axillary lymph node dissection (ALN), with the following equation: h(t) = h0(t) \u00d7 exp (0.695 \u00d7 YY1 + 1.103 \u00d7 STA \u2212 0.503 \u00d7 ALN). ROC analysis of this model showed a better AUC of 0.915, similar sensitivity (83.3%), and much higher specificity (92%). Bioinformatic analysis of public datasets supported these findings in BC, showing YY1 overexpression in multiple cancer types and its association with poor outcomes in BC. These results suggest that YY1 may play a role in tumor progression and serve as a valuable prognostic biomarker in BC. DP combined with molecular data enhanced biomarker accuracy, supporting clinical applications of YY1 in routine diagnostics and personalized therapy. Additionally, developing a combined score based on the modeling of multiple prognostic factors significantly enhanced survival predictions, representing a practical tool for risk stratification and the guidance of therapeutic decisions.<\/jats:p>","DOI":"10.3390\/ijms26188777","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8777","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Significance of Nuclear Yin-Yang Overexpression Evaluated by Immunohistochemistry in Tissue Microarrays and Digital Pathology Analysis: A Useful Prognostic Tool for Breast Cancer"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2718-843X","authenticated-orcid":false,"given":"Mayra","family":"Montecillo-Aguado","sequence":"first","affiliation":[{"name":"Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, Mexico City 06720, Mexico"},{"name":"Laboratorio de Biomedicina Traslacional, Divisi\u00f3n Ciencias de la Salud, Universidad de Guanajuato, Leon Guanajuato 36000, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3985-9149","authenticated-orcid":false,"given":"Giovanny","family":"Soca-Chafre","sequence":"additional","affiliation":[{"name":"Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3274-2718","authenticated-orcid":false,"given":"Gabriela","family":"Antonio-Andres","sequence":"additional","affiliation":[{"name":"Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Belen","family":"Tirado-Rodriguez","sequence":"additional","affiliation":[{"name":"Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9338-6368","authenticated-orcid":false,"given":"Daniel","family":"Hern\u00e1ndez-Cueto","sequence":"additional","affiliation":[{"name":"Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7983-968X","authenticated-orcid":false,"given":"Clara M.","family":"Rivera-Pazos","sequence":"additional","affiliation":[{"name":"Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco A.","family":"Duran-Padilla","sequence":"additional","affiliation":[{"name":"Unidad de Patolog\u00eda Quir\u00fargica, Hospital General de M\u00e9xico Dr. Eduardo Liceaga, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra G.","family":"S\u00e1nchez-Ceja","sequence":"additional","affiliation":[{"name":"Laboratorio de Patolog\u00eda, Facultad de Qu\u00edmico Farmacobiolog\u00eda, Universidad Michoacana de San Nicol\u00e1s de Hidalgo (UMSNH), Morelia 58060, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Berenice","family":"Alcala-Mota-Velazco","sequence":"additional","affiliation":[{"name":"Departamento de Patolog\u00eda, Facultad de Odontolog\u00eda, Universidad Michoacana de San Nicol\u00e1s de Hidalgo (UMSNH), Morelia 58060, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9158-1095","authenticated-orcid":false,"given":"Anel","family":"Gomez-Garcia","sequence":"additional","affiliation":[{"name":"Centro de investigaci\u00f3n Biom\u00e9dica de Michoac\u00e1n, Divisi\u00f3n de Investigaci\u00f3n Cl\u00ednica, Instituto Mexicano del Seguro Social, Morelia 58060, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Gutierrez-Castellanos","sequence":"additional","affiliation":[{"name":"Laboratorio de Patolog\u00eda, Facultad de Qu\u00edmico Farmacobiolog\u00eda, Universidad Michoacana de San Nicol\u00e1s de Hidalgo (UMSNH), Morelia 58060, Mexico"},{"name":"Centro de investigaci\u00f3n Biom\u00e9dica de Michoac\u00e1n, Divisi\u00f3n de Investigaci\u00f3n Cl\u00ednica, Instituto Mexicano del Seguro Social, Morelia 58060, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Huerta-Yepez","sequence":"additional","affiliation":[{"name":"Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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