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Contemporary literature has become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial regulation of the ECM proteome in DCIS has yet to be investigated in relation to IBC. We hypothesized that DCIS and IBC present distinct ECM proteomes that could discriminate between these pathologies. Tissue sections of pure DCIS, mixed DCIS-IBC, or pure IBC (n = 22) with detailed pathological annotations were investigated by multiplexed spatial proteomics. Across tissues, 1,005 ECM peptides were detected in pathologically annotated regions and their surrounding extracellular microenvironments. A comparison of DCIS to IBC pathologies demonstrated 43 significantly altered ECM peptides. Notably, eight fibrillar collagen peptides could distinguish with high specificity and sensitivity between DCIS and IBC. Lesion-targeted proteomic imaging revealed heterogeneity of the ECM proteome surrounding individual DCIS lesions. Multiplexed spatial proteomics reported an invasive cancer field effect, in which DCIS lesions in closer proximity to IBC shared a more similar ECM profile to IBC than distal counterparts. Defining the ECM proteomic microenvironment provides novel molecular insights relating to DCIS and IBC.<\/jats:p>","DOI":"10.3390\/ijms25126748","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T03:46:29Z","timestamp":1718855189000},"page":"6748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Extracellular Microenvironment Alterations in Ductal Carcinoma In Situ and Invasive Breast Cancer Pathologies by Multiplexed Spatial Proteomics"],"prefix":"10.3390","volume":"25","author":[{"given":"Taylor S.","family":"Hulahan","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Spruill","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7019-4187","authenticated-orcid":false,"given":"Elizabeth N.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9645-3407","authenticated-orcid":false,"given":"Yeonhee","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53726, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"West","sequence":"additional","affiliation":[{"name":"Department of Pathology Clinical, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Marks","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Shelley","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard R.","family":"Drake","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4436-555X","authenticated-orcid":false,"given":"Peggi M.","family":"Angel","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Feinberg, J., Wetstone, R., Greenstein, D., and Borgen, P. 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