{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T17:08:56Z","timestamp":1773335336236,"version":"3.50.1"},"reference-count":200,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Center","award":["AWD-P067152"],"award-info":[{"award-number":["AWD-P067152"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although ductal carcinoma in situ (DCIS) diagnoses continue to climb, patient management remains constrained by limitations in recurrence prediction. Conventional histopathology and existing prognostic parameters often inadequately predict local recurrence, leading to over- or under-treatment. Additionally, discourse remains over the clinical implications of margin width as a measure of recurrence risk, demonstrating the limitations of a margin-based model, and motivating our proposal that recurrence risk is dynamic and should be defined by patient-specific, spatially resolved diagnostic biomarkers. This review introduces field cancerization as a framework that may illuminate mechanisms underlying DCIS ipsilateral recurrence and improve clinical decision-making. We propose that the potential drivers of ductal field cancerization span two stages: pre-tumorigenesis and post-tumorigenesis. Pre-tumorigenic events include non-biological and biological exposome factors. Post-tumorigenic drivers include intratumoral and microenvironment-mediated remodeling of adjacent tissues that promote malignancy. This review bridges stage-specific molecular mechanisms to potentially actionable strategies for DCIS patient management\u2014particularly margin assessment and recurrence risk prognostication\u2014while highlighting the critical unmet need to identify biomarkers that measure high-risk field changes. We also emphasize the need to move beyond lesion-centric management toward multivariable prognostic models that include distance-mapped field biomarkers, enabling more precise surgery, improved selection of adjuvant therapy, and safer de-escalation for low-risk patients.<\/jats:p>","DOI":"10.3390\/ijms27062523","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T08:43:31Z","timestamp":1773132211000},"page":"2523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Margin of Error: The Emerging Role of Field Cancerization in Predicting Recurrence Risk of Ductal Carcinoma In Situ"],"prefix":"10.3390","volume":"27","author":[{"given":"Sophia","family":"Hu-Lieskovan","sequence":"first","affiliation":[{"name":"School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7611-6030","authenticated-orcid":false,"given":"Olivia","family":"Banks","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rose","family":"Davidson","sequence":"additional","affiliation":[{"name":"Department of Biology, Westminster University, Salt Lake City, UT 84105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Franklin","sequence":"additional","affiliation":[{"name":"City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Padmashree","family":"Rida","sequence":"additional","affiliation":[{"name":"Science Department, Rowland Hall, Salt Lake City, UT 84102, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4068-2881","authenticated-orcid":false,"given":"Nikita","family":"Jinna","sequence":"additional","affiliation":[{"name":"City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"ref_1","first-page":"e37932","article-title":"Ductal Carcinoma in Situ: A Detailed Review of Current Practices","volume":"15","author":"Kalwaniya","year":"2023","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1038\/s41467-025-57469-3","article-title":"Artificial intelligence for breast cancer screening in mammography (AI-STREAM): Preliminary analysis of a prospective multicenter cohort study","volume":"16","author":"Chang","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_3","first-page":"7","article-title":"Cancer statistics","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA A Cancer J. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.clon.2023.01.019","article-title":"Clinical Outcomes of Conservative Treatment for Low-Risk Ductal Carcinoma in Situ: A Systematic Review and Pooled Analysis","volume":"35","author":"Co","year":"2023","journal-title":"Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/S1470-2045(24)00347-4","article-title":"Postoperative radiotherapy in women with early operable breast cancer (Scottish Breast Conservation Trial): 30-year update of a randomised, controlled, phase 3 trial","volume":"25","author":"Williams","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s10549-017-4410-6","article-title":"Radiotherapy for ductal carcinoma in situ and risk of second non-breast cancers","volume":"166","author":"Withrow","year":"2017","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s10549-018-4803-1","article-title":"Risk of ischemic heart disease after radiotherapy for ductal carcinoma in situ","volume":"171","author":"Wadsten","year":"2018","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3938","DOI":"10.1200\/JCO.2015.60.8588","article-title":"Surgical Excision Without Radiation for Ductal Carcinoma in Situ of the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study","volume":"33","author":"Solin","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3762","DOI":"10.1200\/JCO.2009.26.8847","article-title":"Nomogram for Predicting the Risk of Local Recurrence After Breast-Conserving Surgery for Ductal Carcinoma In Situ","volume":"28","author":"Rudloff","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_11","first-page":"19","article-title":"External validation of Memorial Sloan Kettering Cancer Center nomogram and prediction of optimal candidate for lymph node dissection in clinically localized prostate cancer","volume":"73","author":"Milonas","year":"2020","journal-title":"Central Eur. J. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1199245","DOI":"10.1155\/2022\/1199245","article-title":"The Utility of the Oncotype DX Test for Breast Cancer Patients in an Australian Multidisciplinary Setting","volume":"2022","author":"Choi","year":"2022","journal-title":"Breast J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5974","DOI":"10.1245\/s10434-021-09903-1","article-title":"The Clinical Utility of DCISionRT\u00ae on Radiation Therapy Decision Making in Patients with Ductal Carcinoma In Situ Following Breast-Conserving Surgery","volume":"28","author":"Shah","year":"2021","journal-title":"Ann. Surg. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/s10549-021-06129-3","article-title":"Patterns of invasive recurrence among patients originally treated for ductal carcinoma in situ by breast-conserving surgery versus mastectomy","volume":"186","author":"Pawloski","year":"2021","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.breast.2020.07.008","article-title":"Reoperation rate after breast conserving surgery as quality indicator in breast cancer treatment: A reappraisal","volume":"53","author":"Tamburelli","year":"2020","journal-title":"Breast"},{"key":"ref_16","first-page":"100793","article-title":"Surgical margin and local recurrence of ductal carcinoma in situ","volume":"39","author":"Co","year":"2024","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e076022","DOI":"10.1136\/bmj-2023-076022","article-title":"Association of DCIS size and margin status with risk of developing breast cancer post-treatment: Multinational, pooled cohort study","volume":"383","author":"Schmitz","year":"2023","journal-title":"BMJ"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.breast.2022.03.006","article-title":"Local treatment options for young women with ductal carcinoma in situ: A systematic review and meta-analysis comparing breast conserving surgery with or without adjuvant radiotherapy, and mastectomy","volume":"63","author":"Chien","year":"2022","journal-title":"Breast"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1002\/path.5902","article-title":"Field cancerization in breast cancer","volume":"257","author":"Gadaleta","year":"2022","journal-title":"J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s10911-022-09517-7","article-title":"Ductal Carcinoma in Situ: Molecular Changes Accompanying Disease Progression","volume":"27","author":"Wilson","year":"2022","journal-title":"J. Mammary Gland. Biol. Neoplasia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1387\/ijdb.113385mm","article-title":"The mammary myoepithelial cell","volume":"55","author":"Moumen","year":"2011","journal-title":"Int. J. Dev. Biol."},{"key":"ref_22","first-page":"7","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1002\/path.1048","article-title":"Genetic pathways in the evolution of breast ductal carcinoma in situ","volume":"196","author":"Farabegoli","year":"2002","journal-title":"J. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/gcc.2870140402","article-title":"Genetic alterations in breast cancer","volume":"14","author":"Lidereau","year":"1995","journal-title":"Genes, Chromosom. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1016\/j.ajpath.2015.07.004","article-title":"Myoepithelial Cell Differentiation Markers in Ductal Carcinoma in Situ Progression","volume":"185","author":"Russell","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.humpath.2015.11.003","article-title":"Ductal carcinoma in situ of the breast: The importance of morphologic and molecular interactions","volume":"49","author":"Mardekian","year":"2016","journal-title":"Hum. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.clbc.2015.01.004","article-title":"Phenotypic and Functional Characterization of Ductal Carcinoma In Situ\u2013Associated Myoepithelial Cells","volume":"15","author":"Rohilla","year":"2015","journal-title":"Clin. Breast Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1158\/1078-0432.CCR-13-1504","article-title":"Altered Microenvironment Promotes Progression of Preinvasive Breast Cancer: Myoepithelial Expression of \u03b1v\u03b26 Integrin in DCIS Identifies High-risk Patients and Predicts Recurrence","volume":"20","author":"Allen","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1136\/jclinpath-2019-205939","article-title":"Prognostic significance of cathepsin V (CTSV\/CTSL2) in breast ductal carcinoma in situ","volume":"73","author":"Toss","year":"2019","journal-title":"J. Clin. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1038\/s41416-018-0337-x","article-title":"Prolyl-4-hydroxylase A subunit 2 (P4HA2) expression is a predictor of poor outcome in breast ductal carcinoma in situ (DCIS)","volume":"119","author":"Toss","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/s41416-019-0478-6","article-title":"Ductal carcinoma in situ: To treat or not to treat, that is the question","volume":"121","author":"Lips","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/nm.3886","article-title":"Subclonal diversification of primary breast cancer revealed by multiregion sequencing","volume":"21","author":"Yates","year":"2015","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1002\/path.4840","article-title":"Genome evolution in ductal carcinoma in situ: Invasion of the clones","volume":"241","author":"Casasent","year":"2016","journal-title":"J. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41392-024-01779-3","article-title":"Progression from ductal carcinoma in situ to invasive breast cancer: Molecular features and clinical significance","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1186\/bcr932","article-title":"The changing global patterns of female breast cancer incidence and mortality","volume":"6","author":"Bray","year":"2004","journal-title":"Breast Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1210\/er.2009-0002","article-title":"Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement","volume":"30","author":"Bourguignon","year":"2009","journal-title":"Endocr. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Segovia-Mendoza, M., Palacios-Arreola, M.I., Monroy-Escamilla, L.M., Soto-Pi\u00f1a, A.E., Nava-Castro, K.E., Becerril-Alarc\u00f3n, Y., Camacho-Beiza, R., Aguirre-Quezada, D.E., Cardoso-Pe\u00f1a, E., and Amador-Mu\u00f1oz, O. (2022). Association of Serum Levels of Plasticizers Compounds, Phthalates and Bisphenols, in Patients and Survivors of Breast Cancer: A Real Connection?. Int. J. Environ. Res. Public Heal., 19.","DOI":"10.3390\/ijerph19138040"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1200\/JCO.18.02202","article-title":"Phthalate Exposure and Breast Cancer Incidence: A Danish Nationwide Cohort Study","volume":"37","author":"Ahern","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2858","DOI":"10.1038\/s41598-022-06709-3","article-title":"Association between recurrent breast cancer and phthalate exposure modified by hormone receptors and body mass index","volume":"12","author":"Yang","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Stillwater, B.J., Bull, A.C., Romagnolo, D.F., Neumayer, L.A., Donovan, M.G., and Selmin, O.I. (2020). Bisphenols and Risk of Breast Cancer: A Narrative Review of the Impact of Diet and Bioactive Food Components. Front. Nutr., 7.","DOI":"10.3389\/fnut.2020.581388"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"S16","DOI":"10.1016\/j.amepre.2013.10.031","article-title":"Female Breast Cancer and Alcohol Consumption","volume":"46","author":"Scoccianti","year":"2014","journal-title":"Am. J. Prev. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ctrv.2016.09.010","article-title":"To what extent is alcohol consumption associated with breast cancer recurrence and second primary breast cancer?: A systematic review","volume":"50","author":"Simapivapan","year":"2016","journal-title":"Cancer Treat. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1093\/jnci\/djn514","article-title":"Moderate Alcohol Intake and Cancer Incidence in Women","volume":"101","author":"Allen","year":"2009","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4410","DOI":"10.1200\/JCO.2010.29.2730","article-title":"Alcohol Consumption and Breast Cancer Recurrence and Survival Among Women with Early-Stage Breast Cancer: The Life After Cancer Epidemiology Study","volume":"28","author":"Kwan","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1158\/1055-9965.EPI-10-0388","article-title":"Alcohol Consumption and Risk of Ductal Carcinoma In situ of the Breast in a Cohort of Postmenopausal Women","volume":"19","author":"Kabat","year":"2010","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1080\/01635580903285015","article-title":"Early Intake Appears to Be the Key to the Proposed Protective Effects of Soy Intake Against Breast Cancer","volume":"61","author":"Messina","year":"2009","journal-title":"Nutr. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1001\/jama.2009.1783","article-title":"Soy Food Intake and Breast Cancer Survival","volume":"302","author":"Shu","year":"2009","journal-title":"JAMA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3945\/ajcn.112.035972","article-title":"Soy food intake after diagnosis of breast cancer and survival: An in-depth analysis of combined evidence from cohort studies of US and Chinese women","volume":"96","author":"Nechuta","year":"2012","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_49","first-page":"571","article-title":"Prognostic Significance of Serum Vitamin D Levels in Egyptian Females with Breast Cancer","volume":"19","author":"Ismail","year":"2018","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.1200\/JCO.2008.20.0725","article-title":"Prognostic Effects of 25-Hydroxyvitamin D Levels in Early Breast Cancer","volume":"27","author":"Goodwin","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.jsbmb.2017.10.009","article-title":"Vitamin D deficiency is associated with poor breast cancer prognostic features in postmenopausal women","volume":"174","author":"Pessoa","year":"2017","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3945\/ajcn.2010.30009","article-title":"Vitamin D and breast cancer recurrence in the Women\u2019s Healthy Eating and Living (WHEL) Study","volume":"93","author":"Jacobs","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Augustin, L.S., Libra, M., Crispo, A., Grimaldi, M., De Laurentiis, M., Rinaldo, M., D\u2019aiuto, M., Catalano, F., Banna, G., and Ferrau\u2019, F. (2017). Low glycemic index diet, exercise and vitamin D to reduce breast cancer recurrence (DEDiCa): Design of a clinical trial. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3064-4"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"23320","DOI":"10.1038\/srep23320","article-title":"Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism","volume":"6","author":"Redwan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_55","first-page":"689","article-title":"Risk of recurrence after ductal carcinoma in situ of the breast","volume":"7","author":"Daling","year":"1998","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Lee, H.-M., Lee, H.-J., and Chang, J.-E. (2022). Inflammatory Cytokine: An Attractive Target for Cancer Treatment. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092116"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1111\/cas.15734","article-title":"Inflammatory cytokine-enriched microenvironment plays key roles in the development of breast cancers","volume":"114","author":"Takeuchi","year":"2023","journal-title":"Cancer Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41523-021-00376-9","article-title":"Inflammatory cytokines and distant recurrence in HER2-negative early breast cancer","volume":"8","author":"Sparano","year":"2022","journal-title":"npj Breast Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/S1470-2045(09)70035-X","article-title":"Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: An international consensus statement","volume":"10","author":"Cuzick","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s10549-015-3267-9","article-title":"Effect of COX-2 inhibitors and other non-steroidal inflammatory drugs on breast cancer risk: A meta-analysis","volume":"149","author":"Baeza","year":"2015","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s10549-006-9447-x","article-title":"Psychological distress and fatigue predicted recurrence and survival in primary breast cancer patients","volume":"105","author":"Groenvold","year":"2007","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s12929-023-00903-9","article-title":"Chronic stress in solid tumor development: From mechanisms to interventions","volume":"30","author":"Yan","year":"2023","journal-title":"J. Biomed. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/bcr1831","article-title":"Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: Hypotheses based on epidemiological evidence","volume":"10","author":"Martin","year":"2008","journal-title":"Breast Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1158\/1055-9965.EPI-04-0490","article-title":"The Association of Measured Breast Tissue Characteristics with Mammographic Density and Other Risk Factors for Breast Cancer","volume":"14","author":"Li","year":"2005","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13058-015-0664-2","article-title":"Increased peri-ductal collagen micro-organization may contribute to raised mammographic density","volume":"18","author":"McConnell","year":"2016","journal-title":"Breast Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.crad.2017.11.018","article-title":"Breast density: Why all the fuss?","volume":"73","author":"Vinnicombe","year":"2018","journal-title":"Clin. Radiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/S1470-2045(05)70390-9","article-title":"Mammographic breast density as an intermediate phenotype for breast cancer","volume":"6","author":"Boyd","year":"2005","journal-title":"Lancet Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Zdanowski, A., Sartor, H., Feldt, M., and Skarping, I. (2023). Mammographic density in relation to breast cancer recurrence and survival in women receiving neoadjuvant chemotherapy. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1177310"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s12282-018-0857-5","article-title":"An overview of mammographic density and its association with breast cancer","volume":"25","author":"Nazari","year":"2018","journal-title":"Breast Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1056\/NEJMcp021804","article-title":"Mammographic Screening for Breast Cancer","volume":"348","author":"Fletcher","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1007\/s10549-011-1929-9","article-title":"Mammographic density, parity and age at first birth, and risk of breast cancer: An analysis of four case\u2013control studies","volume":"132","author":"Woolcott","year":"2012","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3830","DOI":"10.1200\/JCO.2009.26.4770","article-title":"Breast Cancer Risk by Breast Density, Menopause, and Postmenopausal Hormone Therapy Use","volume":"28","author":"Kerlikowske","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_73","first-page":"303M","article-title":"Fibrocystic Breast Changes","volume":"93","author":"Faguy","year":"2022","journal-title":"Radiol Technol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Collaborative Group on Hormonal Factors in Breast Cancer (2012). Menarche, menopause, and breast cancer risk: Individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol., 13, 1141\u20131151.","DOI":"10.1016\/S1470-2045(12)70425-4"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/jncimonographs\/lgq034","article-title":"Association Between Patient and Tumor Characteristics with Clinical Outcomes in Women with Ductal Carcinoma In Situ","volume":"2010","author":"Shamliyan","year":"2010","journal-title":"JNCI Monogr."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1093\/jnci\/95.2.100","article-title":"Estrogen and DNA Damage: The Silent Source of Breast Cancer?","volume":"95","author":"Miller","year":"2003","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1093\/jnci\/89.1.76","article-title":"Comparison of Risk Factors for Ductal Carcinoma In Situ and Invasive Breast Cancer","volume":"89","author":"Barclay","year":"1997","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"R35","DOI":"10.1186\/bcr2589","article-title":"Pregnancy-related factors and the risk of breast carcinoma in situand invasive breast cancer among postmenopausal women in the California Teachers Study cohort","volume":"12","author":"Ma","year":"2010","journal-title":"Breast Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Merrill, R.M., and A Folsom, J. (2005). Female breast cancer incidence and survival in Utah according to religious preference, 1985\u20131999. BMC Cancer, 5.","DOI":"10.1186\/1471-2407-5-49"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"608","DOI":"10.2353\/ajpath.2006.050677","article-title":"Remodeling of the Mammary Microenvironment after Lactation Promotes Breast Tumor Cell Metastasis","volume":"168","author":"McDaniel","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_81","unstructured":"Reunanen, N., and K\u00e4h\u00e4ri, V.M. (2000). Matrix Metalloproteinases in Cancer Cell Invasion. Madame Curie Bioscience Database [Internet], Landes Bioscience."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e30831","DOI":"10.1097\/MD.0000000000030831","article-title":"Survival of women with pregnancy-associated breast cancer according to clinical characteristics: A propensity score matching study","volume":"101","author":"Gwak","year":"2022","journal-title":"Medicine"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/s41586-025-09332-0","article-title":"Respiratory viral infections awaken metastatic breast cancer cells in lungs","volume":"645","author":"Chia","year":"2025","journal-title":"Nature"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Yang, S., Zhao, M., and Jia, S. (2023). Macrophage: Key player in the pathogenesis of autoimmune diseases. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1080310"},{"key":"ref_85","first-page":"127","article-title":"Viruses associated with human cancer","volume":"1782","author":"Munger","year":"2008","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e1792","DOI":"10.1038\/cddis.2015.162","article-title":"T-cell exhaustion in the tumor microenvironment","volume":"6","author":"Jiang","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1128\/JVI.02183-15","article-title":"The Missing Link in Epstein-Barr Virus Immune Evasion: The BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II","volume":"90","author":"Quinn","year":"2016","journal-title":"J. Virol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Gabor, F., Jahn, G., Sedmak, D.D., and Sinzger, C. (2020). In vivo Downregulation of MHC Class I Molecules by HCMV Occurs During All Phases of Viral Replication but Is Not Always Complete. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.00283"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Cornel, A.M., Mimpen, I.L., and Nierkens, S. (2020). MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy. Cancers, 12.","DOI":"10.3390\/cancers12071760"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Aloni-Grinstein, R., Charni-Natan, M., Solomon, H., and Rotter, V. (2018). p53 and the Viral Connection: Back into the Future \u2021. Cancers, 10.","DOI":"10.3389\/fendo.2019.00374"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1086\/529379","article-title":"The Role of Regulatory T Cells in Chronic and Acute Viral Infections","volume":"46","author":"Keynan","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1097\/COC.0000000000000239","article-title":"CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition","volume":"39","author":"Buchbinder","year":"2016","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41392-024-01764-w","article-title":"TGF-\u03b2 signaling in health, disease and therapeutics","volume":"9","author":"Deng","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_94","first-page":"381428","article-title":"The Dual Role of TGF\u03b2 in Human Cancer: From Tumor Suppression to Cancer Metastasis","volume":"2012","author":"Lebrun","year":"2012","journal-title":"ISRN Mol. Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1002\/1878-0261.12017","article-title":"Epithelial\u2013mesenchymal transition in tumor metastasis","volume":"11","author":"Yeung","year":"2016","journal-title":"Mol. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5606","DOI":"10.1158\/0008-5472.CAN-11-1194","article-title":"TGF-\u03b2\/SMAD\/GLI2 Signaling Axis in Cancer Progression and Metastasis","volume":"71","author":"Javelaud","year":"2011","journal-title":"Cancer Res."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Tzavlaki, K., and Moustakas, A. (2020). TGF-\u03b2 Signaling. Biomolecules, 10.","DOI":"10.3390\/biom10030487"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0092-8674(03)00432-X","article-title":"Mechanisms of TGF-\u03b2 Signaling from Cell Membrane to the Nucleus","volume":"113","author":"Shi","year":"2003","journal-title":"Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"a022079","DOI":"10.1101\/cshperspect.a022079","article-title":"Transcriptional Control by the SMADs","volume":"8","author":"Hill","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s13045-022-01349-6","article-title":"TGF-\u03b2 signaling in the tumor metabolic microenvironment and targeted therapies","volume":"15","author":"Shi","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Pham, A.H., Mitchell, J., Botto, S., Pryke, K.M., DeFilippis, V.R., and Hancock, M.H. (2021). Human cytomegalovirus blocks canonical TGF\u03b2 signaling during lytic infection to limit induction of type I interferons. PLoS Pathog., 17.","DOI":"10.1101\/2021.02.16.431411"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Silva, J.d.M., Alves, C.E.d.C., and Pontes, G.S. (2024). Epstein-Barr virus: The mastermind of immune chaos. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1297994"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Mahmud, J., Geiler, B.W., Biswas, J., Miller, M.J., Myers, J.E., Matthews, S.M., Wass, A.B., O\u2019Connor, C.M., and Chan, G.C. (2023). Virion-associated US28 rapidly modulates Akt activity to suppress HCMV lytic replication in monocytes. bioRxiv, Update in Sci. Signal.\u00a02024, 17, eadn8727. https:\/\/doi.org\/10.1126\/scisignal.adn8727.","DOI":"10.1126\/scisignal.adn8727"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Jasek-Gajda, E., Jurkowska, H., Jasi\u0144ska, M., and Lis, G.J. (2020). Targeting the MAPK\/ERK and PI3K\/AKT Signaling Pathways Affects NRF2, Trx and GSH Antioxidant Systems in Leukemia Cells. Antioxidants, 9.","DOI":"10.3390\/antiox9070633"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"760","DOI":"10.3390\/v1030760","article-title":"The Human Cytomegalovirus Major Immediate-Early Proteins as Antagonists of Intrinsic and Innate Antiviral Host Responses","volume":"1","author":"Paulus","year":"2009","journal-title":"Viruses"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/B978-0-12-396456-4.00002-X","article-title":"HijAkt: The PI3K\/Akt pathway in virus replication and pathogenesis","volume":"106","author":"Dunn","year":"2012","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1111\/ajt.12725","article-title":"New Cell-Signaling Pathways for Controlling Cytomegalovirus Replication","volume":"14","author":"Roy","year":"2014","journal-title":"Am. J. Transplant."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.2147\/OTT.S91863","article-title":"Links between cancer stem cells and epithelial\u2013 mesenchymal transition","volume":"8","author":"Tang","year":"2015","journal-title":"OncoTargets Ther."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Furler, R.L., Nixon, D.F., Brantner, C.A., Popratiloff, A., and Uittenbogaart, C.H. (2018). TGF-\u03b2 Sustains Tumor Progression through Biochemical and Mechanical Signal Transduction. Cancers, 10.","DOI":"10.20944\/preprints201805.0355.v1"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"521754","DOI":"10.1155\/2014\/521754","article-title":"Transforming Growth Factor-Beta and Matrix Metalloproteinases: Functional Interactions in Tumor Stroma-Infiltrating Myeloid Cells","volume":"2014","author":"Krstic","year":"2014","journal-title":"Sci. World J."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"196","DOI":"10.3109\/08977194.2011.595714","article-title":"TGF-\u03b2 signaling in fibrosis","volume":"29","author":"Biernacka","year":"2011","journal-title":"Growth Factors"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"14679","DOI":"10.2147\/JIR.S539571","article-title":"The Function of the TGF\u03b2 Signaling Pathway in Connective Tissue Diseases: From Biology to Clinical Application","volume":"ume 18","author":"Yuan","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.pbiomolbio.2011.06.006","article-title":"The role of the microenvironment in tumor growth and invasion","volume":"106","author":"Kim","year":"2011","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.chom.2016.04.008","article-title":"Epigenetics and Genetics of Viral Latency","volume":"19","author":"Lieberman","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Murata, T., Sugimoto, A., Inagaki, T., Yanagi, Y., Watanabe, T., Sato, Y., and Kimura, H. (2021). Molecular Basis of Epstein\u2013Barr Virus Latency Establishment and Lytic Reactivation. Viruses, 13.","DOI":"10.3390\/v13122344"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Baasch, S., Ruzsics, Z., and Henneke, P. (2020). Cytomegaloviruses and Macrophages\u2014Friends and Foes From Early on?. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00793"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"7204","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory responses and inflammation-associated diseases in organs","volume":"9","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/imm.12036","article-title":"The immunosuppressive tumour network: Myeloid-derived suppressor cells, regulatory T cells and natural killer T cells","volume":"138","author":"Lindau","year":"2012","journal-title":"Immunology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/2042-4280-2-6","article-title":"Cytomegalovirus-induced immunopathology and its clinical consequences","volume":"2","author":"Varani","year":"2011","journal-title":"Herpesviridae"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Alsaadawe, M., Radman, B.A., Hu, L., Long, J., Luo, Q., Tan, C., Amirat, H.S., Alsaadawi, M., and Lyu, X. (2025). From Viral Infection to Malignancy: The Dual Threat of EBV and COVID-19 in Cancer Development. Viruses, 17.","DOI":"10.3390\/v17091195"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"e000154","DOI":"10.1136\/bmjonc-2023-000154","article-title":"Hypoxia-inducible factor in cancer: From pathway regulation to therapeutic opportunity","volume":"3","author":"Ortmann","year":"2024","journal-title":"BMJ Oncol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.coviro.2017.07.017","article-title":"Epstein\u2013Barr virus: A master epigenetic manipulator","volume":"26","author":"Scott","year":"2017","journal-title":"Curr. Opin. Virol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.bbagrm.2009.08.007","article-title":"Viral-encoded enzymes that target host chromatin functions","volume":"1799","author":"Wei","year":"2009","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Gene Regul. Mech."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s10549-012-2290-3","article-title":"Genomic aberrations in normal tissue adjacent to HER2-amplified breast cancers: Field cancerization or contaminating tumor cells?","volume":"136","author":"Sadanandam","year":"2012","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1002\/ijc.21815","article-title":"Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors","volume":"119","author":"Heaphy","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1038\/s41467-017-01027-z","article-title":"Comprehensive analysis of normal adjacent to tumor transcriptomes","volume":"8","author":"Aran","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"20567","DOI":"10.1038\/srep20567","article-title":"Transcriptional Profiles from Paired Normal Samples Offer Complementary Information on Cancer Patient Survival\u2014Evidence from TCGA Pan-Cancer Data","volume":"6","author":"Huang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1158\/1541-7786.MCR-10-0424","article-title":"Breast Field Cancerization: Isolation and Comparison of Telomerase-Expressing Cells in Tumor and Tumor Adjacent, Histologically Normal Breast Tissue","volume":"9","author":"Trujillo","year":"2011","journal-title":"Mol. Cancer Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1158\/1078-0432.166.11.1","article-title":"Promoter Hypermethylation in Benign Breast Epithelium in Relation to Predicted Breast Cancer Risk","volume":"11","author":"Lewis","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/S0002-9440(10)64880-8","article-title":"Quantitative Assessment of Promoter Hypermethylation during Breast Cancer Development","volume":"160","author":"Lehmann","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1101\/gr.187823.114","article-title":"Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer","volume":"25","author":"Forsberg","year":"2015","journal-title":"Genome Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/S0959-8049(01)00118-6","article-title":"Loss of heterozygosity in tumour-adjacent normal tissue of breast and bladder cancer","volume":"37","author":"Louhelainen","year":"2001","journal-title":"Eur. J. Cancer"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41523-020-00182-9","article-title":"Characterization of four subtypes in morphologically normal tissue excised proximal and distal to breast cancer","volume":"6","author":"Gadaleta","year":"2020","journal-title":"npj Breast Cancer"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1038\/sj.bjc.6605576","article-title":"Gene expression in histologically normal epithelium from breast cancer patients and from cancer-free prophylactic mastectomy patients shares a similar profile","volume":"102","author":"Graham","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/path.1973","article-title":"Quantitative analysis of allele imbalance supports atypical ductal hyperplasia lesions as direct breast cancer precursors","volume":"209","author":"Larson","year":"2006","journal-title":"J. Pathol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"R51","DOI":"10.1186\/bcr3152","article-title":"Gene expression in extratumoral microenvironment predicts clinical outcome in breast cancer patients","volume":"14","author":"Pirone","year":"2012","journal-title":"Breast Cancer Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"16007","DOI":"10.1038\/npjbcancer.2016.7","article-title":"DNA defects, epigenetics, and gene expression in cancer-adjacent breast: A study from The Cancer Genome Atlas","volume":"2","author":"Cherniack","year":"2016","journal-title":"npj Breast Cancer"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1002\/ijc.25788","article-title":"Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors","volume":"129","author":"Trujillo","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13058-019-1165-5","article-title":"A whole slide image-based machine learning approach to predict ductal carcinoma in situ (DCIS) recurrence risk","volume":"21","author":"Klimov","year":"2019","journal-title":"Breast Cancer Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/25292","article-title":"Genetic instabilities in human cancers","volume":"396","author":"Lengauer","year":"1998","journal-title":"Nature"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s10549-004-1424-7","article-title":"Genomic patterns of allelic imbalance in disease free tissue adjacent to primary breast carcinomas","volume":"88","author":"Ellsworth","year":"2004","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_142","first-page":"1591","article-title":"Genetically abnormal clones in histologically normal breast tissue","volume":"152","author":"Larson","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S0002-9440(10)64180-6","article-title":"Loss of Heterozygosity or Allele Imbalance in Histologically Normal Breast Epithelium Is Distinct from Loss of Heterozygosity or Allele Imbalance in Co-Existing Carcinomas","volume":"161","author":"Larson","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_144","first-page":"1000","article-title":"Increased risk of local recurrence is associated with allelic loss in normal lobules of breast cancer patients","volume":"62","author":"Li","year":"2002","journal-title":"Cancer Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0959-8049(98)00343-8","article-title":"The risk of breast cancer following reproductive surgery","volume":"35","author":"Kreiger","year":"1999","journal-title":"Eur. J. Cancer"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1080\/15476286.2021.1885189","article-title":"Exosomes provide unappreciated carrier effects that assist transfers of their miRNAs to targeted cells; I. They are \u2018The Elephant in the Room\u2019","volume":"18","author":"Askenase","year":"2021","journal-title":"RNA Biol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S0960-0760(03)00377-7","article-title":"Genotoxic metabolites of estradiol in breast: Potential mechanism of estradiol induced carcinogenesis","volume":"86","author":"Yue","year":"2003","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/S1470-2045(04)01653-5","article-title":"Genomic instability in histologically normal breast tissues: Implications for carcinogenesis","volume":"5","author":"Ellsworth","year":"2004","journal-title":"Lancet Oncol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S0959-8049(02)00248-4","article-title":"Angiogenesis and invasive recurrence in ductal carcinoma in situ of the breast","volume":"39","author":"Teo","year":"2003","journal-title":"Eur. J. Cancer"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.1158\/1078-0432.CCR-19-1272","article-title":"A Quantitative Centrosomal Amplification Score Predicts Local Recurrence of Ductal Carcinoma In Situ","volume":"26","author":"Mittal","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Denu, R.A., Zasadil, L.M., Kanugh, C., Laffin, J., Weaver, B.A., and Burkard, M.E. (2016). Centrosome amplification induces high grade features and is prognostic of worse outcomes in breast cancer. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2083-x"},{"key":"ref_152","first-page":"3","article-title":"G1 and S-phase checkpoints, chromosome instability, and cancer","volume":"280","author":"Nojima","year":"2004","journal-title":"Methods Mol. Biol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"36137","DOI":"10.18632\/oncotarget.16661","article-title":"Glioma stem cells-derived exosomes promote the angiogenic ability of endothelial cells through miR-21\/VEGF signal","volume":"8","author":"Sun","year":"2017","journal-title":"Oncotarget"},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"King, H.W., Michael, M.Z., and Gleadle, J.M. (2012). Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-421"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1016\/j.celrep.2020.01.073","article-title":"Glioma-Derived miRNA-Containing Extracellular Vesicles Induce Angiogenesis by Reprogramming Brain Endothelial Cells","volume":"30","author":"Lucero","year":"2020","journal-title":"Cell Rep."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/ncb869","article-title":"PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1\/Chk2","volume":"4","author":"Yang","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1080\/15592294.2020.1747748","article-title":"Enrichment of CpG island shore region hypermethylation in epigenetic breast field cancerization","volume":"15","author":"Muse","year":"2020","journal-title":"Epigenetics"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"6626","DOI":"10.1158\/1078-0432.CCR-06-0467","article-title":"Mapping Geographic Zones of Cancer Risk with Epigenetic Biomarkers in Normal Breast Tissue","volume":"12","author":"Yan","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.ebiom.2018.04.025","article-title":"DNA Methylation Patterns in Normal Tissue Correlate more Strongly with Breast Cancer Status than Copy-Number Variants","volume":"31","author":"Gao","year":"2018","journal-title":"eBioMedicine"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.cell.2008.03.027","article-title":"The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells","volume":"133","author":"Mani","year":"2008","journal-title":"Cell"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1002\/jso.24469","article-title":"Towards a personalized surgical margin for breast conserving surgery\u2014Implications of field cancerization in local recurrence","volume":"115","author":"Lebya","year":"2017","journal-title":"J. Surg. Oncol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"5451","DOI":"10.1002\/jcp.27486","article-title":"An overview of microRNAs: Biology, functions, therapeutics, and analysis methods","volume":"234","author":"Saliminejad","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Shen, S., Sun, Q., Liang, Z., Cui, X., Ren, X., Chen, H., Zhang, X., and Zhou, Y. (2014). A Prognostic Model of Triple-Negative Breast Cancer Based on miR-27b-3p and Node Status. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100664"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"28347","DOI":"10.3390\/ijms161226090","article-title":"miRNAs and Other Epigenetic Changes as Biomarkers in Triple Negative Breast Cancer","volume":"16","author":"Mathe","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"103012","DOI":"10.1016\/j.isci.2021.103012","article-title":"Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumor growth","volume":"24","author":"McKee","year":"2021","journal-title":"iScience"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"3539","DOI":"10.1158\/0008-5472.CAN-19-1698","article-title":"The Gut Microbiome: A New Player in Breast Cancer Metastasis","volume":"79","author":"Ingman","year":"2019","journal-title":"Cancer Res."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"5039","DOI":"10.1128\/AEM.01235-16","article-title":"The Microbiota of Breast Tissue and Its Association with Breast Cancer","volume":"82","author":"Urbaniak","year":"2016","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_168","doi-asserted-by":"crossref","unstructured":"Xuan, C., Shamonki, J.M., Chung, A., DiNome, M.L., Chung, M., Sieling, P.A., and Lee, D.J. (2014). Microbial Dysbiosis Is Associated with Human Breast Cancer. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0083744"},{"key":"ref_169","doi-asserted-by":"crossref","unstructured":"Banerjee, S., Tian, T., Wei, Z., Shih, N., Feldman, M.D., Peck, K.N., DeMichele, A.M., Alwine, J.C., and Robertson, E.S. (2018). Distinct Microbial Signatures Associated with Different Breast Cancer Types. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.00951"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.ccell.2016.10.009","article-title":"Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis","volume":"30","author":"Becker","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s12967-021-03215-4","article-title":"The role of Exosomal miRNAs in cancer","volume":"20","author":"Li","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/dom.13027","article-title":"Exosomes as new players in metabolic organ cross-talk","volume":"19","author":"Guay","year":"2017","journal-title":"Diabetes, Obes. Metab."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.smim.2017.12.003","article-title":"Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment","volume":"35","author":"Whiteside","year":"2018","journal-title":"Semin. Immunol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/s41467-017-02583-0","article-title":"Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer","volume":"9","author":"Fang","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/cdd.2015.78","article-title":"Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling","volume":"23","author":"Tang","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"7399","DOI":"10.1038\/s41388-019-0952-x","article-title":"An miR-340-5p-macrophage feedback loop modulates the progression and tumor microenvironment of glioblastoma multiforme","volume":"38","author":"Liu","year":"2019","journal-title":"Oncogene"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s13105-018-0622-4","article-title":"Effects of exosomes from LPS-activated macrophages on adipocyte gene expression, differentiation, and insulin-dependent glucose uptake","volume":"74","author":"Samblas","year":"2018","journal-title":"J. Physiol. Biochem."},{"key":"ref_178","first-page":"1","article-title":"Exosomal miRNA profile as complementary tool in the diagnostic and prediction of treatment response in localized breast cancer under neoadjuvant chemotherapy","volume":"21","author":"Ortega","year":"2019","journal-title":"Breast Cancer Res."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1111\/cas.13697","article-title":"Exosomes in cancer development and clinical applications","volume":"109","author":"Tai","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_180","doi-asserted-by":"crossref","unstructured":"Zhao, Z., Yang, S., Zhou, A., Li, X., Fang, R., Zhang, S., Zhao, G., and Li, P. (2021). Small Extracellular Vesicles in the Development, Diagnosis, and Possible Therapeutic Application of Esophageal Squamous Cell Carcinoma. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.732702"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/s41556-018-0083-6","article-title":"Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells","volume":"20","author":"Yan","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41389-017-0011-9","article-title":"The hypoxic tumour microenvironment","volume":"7","author":"Petrova","year":"2018","journal-title":"Oncogenesis"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.cytogfr.2019.12.010","article-title":"Tumor-derived extracellular vesicles and microRNAs: Functional roles, diagnostic, prognostic and therapeutic options","volume":"51","author":"Pontecorvi","year":"2020","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1186\/s13046-018-0965-2","article-title":"Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts","volume":"37","author":"Zhou","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13046-020-01570-6","article-title":"Exosomal miRNAs in tumor microenvironment","volume":"39","author":"Tan","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.cell.2024.11.009","article-title":"A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor","volume":"188","author":"Mei","year":"2024","journal-title":"Cell"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"9621","DOI":"10.1158\/0008-5472.CAN-10-1722","article-title":"Cancer Exosomes Trigger Fibroblast to Myofibroblast Differentiation","volume":"70","author":"Webber","year":"2010","journal-title":"Cancer Res."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1038\/s41418-018-0205-5","article-title":"Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma","volume":"26","author":"Fattore","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_189","doi-asserted-by":"crossref","unstructured":"Fernando, M.R., Jiang, C., Krzyzanowski, G.D., and Ryan, W.L. (2017). New evidence that a large proportion of human blood plasma cell-free DNA is localized in exosomes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183915"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"1002322","DOI":"10.37349\/etat.2025.1002322","article-title":"Role of exosomes in transforming growth factor-\u03b2-mediated cancer cell plasticity and drug resistance","volume":"6","author":"Ruksha","year":"2025","journal-title":"Explor. Target. Antitumor Ther."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10495-010-0534-4","article-title":"Survivin is released from cancer cells via exosomes","volume":"16","author":"Khan","year":"2010","journal-title":"Apoptosis"},{"key":"ref_192","first-page":"43","article-title":"The emerging role of exosomes in survivin secretion","volume":"30","author":"Khan","year":"2014","journal-title":"Histol. Histopathol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/s41586-019-1763-5","article-title":"Circular ecDNA promotes accessible chromatin and high oncogene expression","volume":"575","author":"Wu","year":"2019","journal-title":"Nature"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/nature21356","article-title":"Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity","volume":"543","author":"Turner","year":"2017","journal-title":"Nature"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1042\/BST20221045","article-title":"Extrachromosomal DNA (ecDNA): An origin of tumor heterogeneity, genomic remodeling, and drug resistance","volume":"50","author":"Pecorino","year":"2022","journal-title":"Biochem. Soc. Trans."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/1878-0261.12777","article-title":"DNA in extracellular vesicles: Biological and clinical aspects","volume":"15","author":"Elzanowska","year":"2020","journal-title":"Mol. Oncol."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/j.cell.2016.11.005","article-title":"The Hippo Pathway Kinases LATS1\/2 Suppress Cancer Immunity","volume":"167","author":"Moroishi","year":"2016","journal-title":"Cell"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"56279","DOI":"10.18632\/oncotarget.10783","article-title":"Procoagulant and immunogenic properties of melanoma exosomes, microvesicles and apoptotic vesicles","volume":"7","author":"Saunderson","year":"2016","journal-title":"Oncotarget"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/s41422-018-0060-4","article-title":"Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth","volume":"28","author":"Yang","year":"2018","journal-title":"Cell Res."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cellimm.2014.09.004","article-title":"Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203","volume":"292","author":"Zhou","year":"2014","journal-title":"Cell. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2523\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T05:33:59Z","timestamp":1773293639000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2523"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,10]]},"references-count":200,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062523"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062523","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,10]]}}}