{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:37:36Z","timestamp":1788345456698,"version":"build-2803163510"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"8","funder":[{"DOI":"10.13039\/100011541","name":"Division of Cancer Epidemiology and Genetics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011541","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NCI","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"publisher","award":["BCRF-23-140"],"award-info":[{"award-number":["BCRF-23-140"]}],"id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"publisher","award":["R01CA282725"],"award-info":[{"award-number":["R01CA282725"]}],"id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NCI","doi-asserted-by":"publisher","award":["P01CA240685"],"award-info":[{"award-number":["P01CA240685"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Aggressive (typically high-grade) breast cancers (BCs) remain major contributors to BC-related mortality globally. The tissue changes underpinning their etiology and outcomes, however, remain poorly characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Spatially resolved machine-learning algorithms were used to characterize \u201cstromal disruption\u201d as a morphological metric of reduced\/altered extracellular matrix and increased immune, inflammatory, and\/or wound response-related processes in normal, benign breast disease (BBD), and invasive hematoxylin and eosin (H&amp;E)-stained breast tissues. Associations of stromal disruption with BC etiologic factors were assessed among 4023 healthy breast tissue donors, its impact on BC incidence was assessed among 974 BBD patients in a nested case\u2013control study, while its prognostic associations were assessed in 4 BC patient cohorts (n\u2009=\u20094223).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Epidemiologic risk factors for aggressive BC, including younger age, multiparity, Black race, obesity, and family history, demonstrated strong associations with increasing stromal disruption in H&amp;E sections prior to tumor development. Substantial stromal disruption in BBD H&amp;E was associated with \u223c4-fold increased risk of aggressive (high-grade) BC and \u223c3 years shorter latency from BBD to BC diagnosis, independently of BBD histology. Across BC cohorts, stromal disruption in H&amp;E was associated with aggressive (mostly high-grade) tumor phenotypes and with markedly poor prognosis among ER-positive patients, irrespective of histology. The immunobiology of stromal disruption reflected heightened innate (CD68+), adaptive (CD3+CD4+, CD3+CD8+), immunoregulatory (CD3+CD4+FOXP3+), immune escape (PD1+PDL1+), endothelial (CD31+), and myofibroblast (\u03b1-SMA+) marker expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings highlight the active stromal role in aggressive BC etiology and outcomes, opening possibilities for readily identifying high-risk women across the BC continuum that may benefit from stroma-centric preventative or therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jnci\/djaf070","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T06:48:12Z","timestamp":1742712492000},"page":"1673-1688","source":"Crossref","is-referenced-by-count":9,"title":["Unraveling the role of stromal disruption in aggressive breast cancer etiology and outcomes"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3728-6535","authenticated-orcid":false,"given":"Mustapha","family":"Abubakar","sequence":"first","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health (NIH) , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1ire A","family":"Duggan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Calgary , Calgary, AB,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5894-7510","authenticated-orcid":false,"given":"Shaoqi","family":"Fan","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health (NIH) , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-2698","authenticated-orcid":false,"given":"Ruth M","family":"Pfeiffer","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health (NIH) , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Molecular and Digital Pathology Laboratory, Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc. , Frederick, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karun","family":"Mutreja","sequence":"additional","affiliation":[{"name":"Molecular and Digital Pathology Laboratory, Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc. , Frederick, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Klein","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health (NIH) , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hela","family":"Koka","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health (NIH) , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas U","family":"Ahearn","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health (NIH) , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill E","family":"Henry","sequence":"additional","affiliation":[{"name":"Biospecimen Collection and Banking Core, Susan G. Komen Tissue Bank at the IU Simon Comprehensive Cancer Center , Indianapolis, IN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L","family":"Sprague","sequence":"additional","affiliation":[{"name":"University of Vermont College of Medicine and Vermont Cancer Center , Burlington, VT,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela M","family":"Vacek","sequence":"additional","affiliation":[{"name":"University of Vermont College of Medicine and Vermont Cancer Center , Burlington, VT,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald L","family":"Weaver","sequence":"additional","affiliation":[{"name":"University of Vermont College of Medicine and Vermont Cancer Center , Burlington, VT,","place":["United 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Accra,","place":["Ghana"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5100-623X","authenticated-orcid":false,"given":"Jonine D","family":"Figueroa","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health (NIH) , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong R","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health (NIH) , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1033-2650","authenticated-orcid":false,"given":"Montserrat","family":"Garcia-Closas","sequence":"additional","affiliation":[{"name":"Division of Cancer Genetics and Epidemiology, Institute of Cancer Research London , 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