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Most male breast cancers are treated using female-based protocols, making a higher-resolution transcriptional and epigenetic map essential for improved intervention. Matched single-cell RNA-seq and ATAC-seq profiles were generated from two treatment-naïve male breast tumors to compare gene expression across immune, stromal, and malignant compartments and reveal therapeutic candidates. MYC target and mTORC1 signaling programs were elevated in malignant cells, while enhancer rewiring connected chromatin accessibility changes to gene expression, including unannotated enhancers and super-enhancer regulation of LAMB3 and CD47.",{"@graph":69,"@context":122},[70,84,105],{"@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/single-cell-transcriptional-and-epigenetic-profiles-of-male-breast-cancer-nominate-salient-cancer-specific-enhancers/386251/",{"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/single-cell-transcriptional-and-epigenetic-profiles-of-male-breast-cancer-nominate-salient-cancer-specific-enhancers/386251.png","ImageObject",300,407,{"name":92,"@type":93},"Chumphorn","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-28","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is targeted therapy for male breast cancer difficult to establish?","Question",{"text":112,"@type":113},"Limited male-specific data makes it hard to define transcriptional and epigenetic targets for therapy development. 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Regner 1,2, Aatish Thennavan 1,3, Philip M. Spanheimer 1,4 and Hector L. Franco 1,2,5, *  \nCitation: Kim, H.; Wisniewska, K.; Regner, M.J.; Thennavan, A.;  \nSpanheimer, P.M.; Franco, H.L. Single-Cell Transcriptional and Epigenetic Proﬁles of Male Breast Cancer Nominate Salient  \nCancer-Speciﬁc Enhancers. Int. J. Mol. Sci. 2023, 24, 13053. [https://](https://)  \n[doi.org/10.3390/ijms241713053](doi.org/10.3390/ijms241713053)[ ](doi.org/10.3390/ijms241713053)Academic Editors: Nicoletta Cordani and Monica Iorﬁda  \nReceived: 21 July 2023  \nRevised: 18 August 2023  \nAccepted: 19 August 2023  \nPublished: 22 August 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA  \n2 Bioinformatics and Computational Biology Graduate Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA  \n3 Oral and Craniofacial Biomedicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA  \n4 Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA  \n5 Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA  \n* [Correspondence: hfranco@med.unc.edu](Correspondence: hfranco@med.unc.edu)  \n† These authors contributed equally to this work.  \nAbstract: Male breast cancer represents about 1% of all breast cancer diagnoses and, although there are some similarities between male and female breast cancer, the paucity of data available on male breast cancer makes it difﬁcult to establish targeted therapies. To date, most male breast cancers (MBCs) are treated according to protocols established for female breast cancer (FBC) . Thus, deﬁning the transcriptional and epigenetic landscape of MBC with improved resolution is critical for developing better avenues for therapeutic intervention. In this study, we present matched transcriptional (scRNA-seq) and epigenetic (scATAC-seq) proﬁles at single-cell resolution of two treatment naïve MBC tumors processed immediately after surgical resection. These data enable the detection of differentially expressed genes between male and female breast tumors across immune, stromal, and malignant cell types, to highlight several genes that may have therapeutic implications. Notably, MYC target genes and mTORC1 signaling genes were signiﬁcantly upregulated in the malignant cells of MBC compared to the female counterparts. To understand how the regulatory landscape of MBC gives rise to these male-speciﬁc gene expression patterns, we leveraged the scATAC-seq data to systematically link changes in chromatin accessibility to changes in gene expression within each cell type. We observed cancer-speciﬁc rewiring of several salient enhancers and posit that these enhancers have a higher regulatory load than lineage-speciﬁc enhancers. We highlight two examples of previously unannotated cancer-cell-speciﬁc enhancers of ANXA2 and PRDX4 gene expression and show evidence for super-enhancer regulation of LAMB3 and CD47 in male breast cancer cells. Overall, this dataset annotates clinically relevant regulatory networks in male breast tumors, providing a useful resource that expands our current understanding of the gene expression programs that underlie the biology of MBC.  \nKeywords: breast cancer; male breast cancer; single-cell genomics; scRNA-seq; scATAC-seq; intratumoral heterogeneity; gene regulation;","cbCaivHnchyNUAlU","https://ap.wps.com/l/cbCaivHnchyNUAlU","pdf",5288567,"English","# Abstract\n# Introduction\n## Male breast cancer background and clinical context\n## Current treatment limitations and need for targeted therapies\n# Dataset and single-cell approaches","[{\"question\":\"Why is targeted therapy for male breast cancer difficult to establish?\",\"answer\":\"Limited male-specific data makes it hard to define transcriptional and epigenetic targets for therapy development. As a result, treatment often follows protocols established for female breast cancer.\"},{\"question\":\"What single-cell data were generated in this study?\",\"answer\":\"The study provides matched single-cell transcriptional profiles (scRNA-seq) and epigenetic profiles (scATAC-seq) at single-cell resolution from two treatment-naïve male breast cancer tumors.\"},{\"question\":\"Which molecular programs were found to be upregulated in male breast cancer malignant cells?\",\"answer\":\"MYC target genes and mTORC1 signaling genes were significantly upregulated in the malignant cells of male breast cancer compared with female counterparts.\"}]","Single-Cell Transcriptional and Epigenetic Proﬁles of Male Breast Cancer Nominate Salient Cancer-Speciﬁc Enhancers | PDF",1790272935]