Single-Cell Transcriptional and Epigenetic Profiles of Male Breast Cancer Nominate Salient Cancer-Specific Enhancers

被引:2
|
作者
Kim, Hyunsoo [1 ]
Wisniewska, Kamila [1 ]
Regner, Matthew J. [1 ,2 ]
Thennavan, Aatish [1 ,3 ]
Spanheimer, Philip M. [1 ,4 ]
Franco, Hector L. [1 ,2 ,5 ]
机构
[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Bioinformat & Computat Biol Grad Program, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Oral & Craniofacial Biomed Program, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Div Surg Oncol, Chapel Hill, NC 27599 USA
[5] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA
关键词
breast cancer; male breast cancer; single-cell genomics; scRNA-seq; scATAC-seq; intratumoral heterogeneity; gene regulation; chromatin accessibility; enhancer elements; CHROMATIN ACCESSIBILITY; SUPER-ENHANCERS; MUTATION;
D O I
10.3390/ijms241713053
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 naive 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.
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页数:20
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