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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,7,30]]},"abstract":"<jats:p>\n                    Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity \u2013 e.g., MDLC with triple-negative breast cancer (TNBC) or basal ductal and estrogen receptor positive (ER+) luminal lobular regions, distinct enrichment of cell cycle arrest\/senescence and oncogenic (ER and\n                    <jats:italic>MYC<\/jats:italic>\n                    ) signatures, genetic and epigenetic\n                    <jats:italic>CDH1<\/jats:italic>\n                    inactivation in lobular but not ductal regions, and single-cell ductal and lobular subpopulations with unique oncogenic signatures further highlighting intraregional heterogeneity. Altogether, we demonstrated that the intratumoral morphological\/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2322068121","type":"journal-article","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T13:48:47Z","timestamp":1721742527000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":19,"title":["Spatial molecular profiling of mixed invasive ductal and lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4756-4535","authenticated-orcid":false,"given":"Osama Shiraz","family":"Shah","sequence":"first","affiliation":[{"name":"Womens Cancer Research Center at University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center and Magee Women\u2019s Research Institute, Pittsburgh, PA 15213"},{"name":"Integrative Systems Biology Program, University of Pittsburgh School of Medicine, Pittsburgh PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azadeh","family":"Nasrazadani","sequence":"additional","affiliation":[{"name":"Womens Cancer Research Center at University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center and Magee Women\u2019s Research Institute, Pittsburgh, PA 15213"},{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7504-867X","authenticated-orcid":false,"given":"Julia","family":"Foldi","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Womens Cancer Research Center at University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center and Magee Women\u2019s Research Institute, Pittsburgh, PA 15213"},{"name":"Department of Pharmacology &amp; 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