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From over 800,000 cells, 41 epithelial, immune, and stromal subclusters are resolved, with cluster contributions varying by tissue natural history. Age, parity, and germline mutations alter homeostatic cellular states in distinct ways. Immune cells from BRCA1 or BRCA2 carriers show gene-expression patterns consistent with immune exhaustion, validated by immunohistochemistry. The resource supports early detection and prevention of breast cancer.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-single-cell-atlas-enables-mapping-of-homeostatic-cellular-shifts-in-the-adult-human-breast/330476/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/a-single-cell-atlas-enables-mapping-of-homeostatic-cellular-shifts-in-the-adult-human-breast/330476.png","ImageObject",300,407,{"name":92,"@type":93},"Ava Thompson","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-09","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",14,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"How was the human breast cell atlas constructed in the study?","Question",{"text":113,"@type":114},"The atlas was assembled using single-cell RNA sequencing from 55 donors who underwent reduction mammoplasties or risk reduction mastectomies, generating data from more than 800,000 cells.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What did the study identify in terms of cell diversity?",{"text":118,"@type":114},"Across epithelial, immune, and stromal compartments, the work identified 41 cell subclusters and showed that their contributions vary with the tissue’s natural history.",{"name":120,"@type":111,"acceptedAnswer":121},"What immune changes were observed in BRCA1 or BRCA2 carriers?",{"text":122,"@type":114},"Immune cells from BRCA1 or BRCA2 carriers displayed a distinct gene-expression signature indicative of potential immune exhaustion, validated by immunohistochemistry.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},330476,1790876090,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},1649267921044,"https://us-avatar.wpscdn.com/avatar/1800007509477c92dfb?_k=1786009248482753345","nature genetics  \nArticle [https://doi.org/10.1038/s41588-024-01688-9](https://doi.org/10.1038/s41588-024-01688-9)  \nA single-cell atlas enables mapping of homeostatic cellular shiftsin the adult human breast  \nReceived: 28 March 2023  \nAccepted: 9 February 2024  \n\n| Published online: 28 March 2024 |\n| --- |\n|  Check for updates |\n\nAustin D. Reed1,2,10, Sara Pensa1,2,10, Adi Steif3, Jack Stenning  1,2, Daniel J. Kunz  4, Linsey J. Porter1,2, Kui Hua  3, Peng He  4,5, Alecia-Jane Twigger1,2, Abigail J. Q. Siu  1,2, Katarzyna Kania  3,  \nRachel Barrow-McGee6, Iain Goulding6, Jennifer J. Gomm6, Valerie Speirs7,8, J Louise Jones6, John C. Marioni  3,4,5,9  & Walid T. Khaled  1,2   \nHere we use single-cell RNA sequencing to compile a human breast cell atlas assembled from 55 donors that had undergone reduction mammoplasties or risk reduction mastectomies. From more than 800,000 cells we identified 41 cell subclusters across the epithelial, immune and stromal compartments. The contribution of these different clusters varied according to the natural history of the tissue. Age, parity and germline mutations, known to modulate the risk of developing breast cancer, affected the homeostatic cellular state of the breast indifferent ways. We found that immune cells from BRCA1 orBRCA2 carriershada distinct gene expression signature indicative of potential immune exhaustion, which was validated by immunohistochemistry. This suggests that immune-escape mechanisms could manifest in non-cancerous tissues very early during tumor initiation. This atlas isa rich resource that can be used to inform novel approaches for early detection and prevention of breast cancer.  \nOne of the biggest challenges in treating breast cancer is the heterogeneous nature of the disease1. We have limited understanding of how early divergences from the homeostatic breast subtypes lead to tumor heterogeneity. While large-scale cancer genomic studies indicate that different breast cancer subtypes are enriched for certain mutations2, not all phenotype variability and tumor behavior can be explained by mutations alone. Studies in mice have shown that the cell-of-origin may contribute to the phenotype of the resulting tumor3. Defining which cell type leads to which kind of tumor is complicated by a growing list of environmental and epidemiological risk factors, such as age, which not only affect overall incidence, but also outcome4. Such risk  \nfactors can themselves be modulated by other factors; for example, the age-dependent risk in breast cancer is greatly reduced by pregnancy early in life5, whereas predisposing germline mutations (for example, BRCA1 orBRCA2) greatly increases age-associated risk6. How these risk factors interact and impact tissue homeostasis remains tobe fully understood. Todo this, it is crucial to characterize cell types and cellular states present under different physiological conditions.  \nTo tackle this problem, studies in the mouse have leveraged single-cell genomics (that is, single-cell RNA sequencing (scRNA-seq)) to determine the gene expression profile of individual mammary epithelial cells across embryonic and adult developmental stages7–10.  \n1Department of Pharmacology, University of Cambridge, Cambridge, UK. 2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. 3CRUK, Cambridge Institute, University of Cambridge, Cambridge, UK. 4EMBL European Bioinformatics Institute, Hinxton, UK.  \n5Sanger Institute, Hinxton, UK. 6Breast Cancer Now Tissue Bank, Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of London, London, UK. 7Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK. 8Aberdeen Cancer Centre, Aberdeen, UK. 9Present address: Genentech, San Francisco, CA, USA. 10These authors contributed equally: Austin D. Reed, Sara Pensa. [e-mail:](e-mail: marioni@ebi.ac.uk)[ marioni@ebi.ac.uk](e-mail: marioni@ebi.ac.uk); [wtk22@cam.ac.uk](wtk22@cam.ac.uk)  \n","cbCaigzvZ0VV7Wxm","https://ap.wps.com/l/cbCaigzvZ0VV7Wxm","pdf",18704374,29,"English","# Overview and experimental design\n## Human breast atlas construction\n# Cellular states and risk factors\n## Homeostatic shifts across donors\n## BRCA1/BRCA2 immune signatures\n# Background and motivation\n## Challenges in breast cancer heterogeneity\n## Stromal compartment and microenvironment","[{\"question\":\"How was the human breast cell atlas constructed in the study?\",\"answer\":\"The atlas was assembled using single-cell RNA sequencing from 55 donors who underwent reduction mammoplasties or risk reduction mastectomies, generating data from more than 800,000 cells.\"},{\"question\":\"What did the study identify in terms of cell diversity?\",\"answer\":\"Across epithelial, immune, and stromal compartments, the work identified 41 cell subclusters and showed that their contributions vary with the tissue’s natural history.\"},{\"question\":\"What immune changes were observed in BRCA1 or BRCA2 carriers?\",\"answer\":\"Immune cells from BRCA1 or BRCA2 carriers displayed a distinct gene-expression signature indicative of potential immune exhaustion, validated by immunohistochemistry.\"}]","A single-cell atlas enables mapping of homeostatic cellular shifts in the adult human breast | PDF",1789989104,73]