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

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

Molecular signatures of in situ to invasive progression for basal-like breast cancers: An integrated mouse model and human DCIS study

Abstract Ductal carcinoma in situ (DCIS) of the breast is a non-obligate precursor of Invasive Ductal Carcinoma (IDC) and thus the identification of features that may predict DCIS progression would be of potential clinical value. Experimental mouse models can be used to address this challenge by studying DCIS-to-IDC biology. Here we utilize single cell RNA sequencing (scRNAseq) on the C3Tag genetically engineered mouse model that forms DCIS-like precursor lesions and for which many lesions progress into end-stage basal-like molecular subtype IDC. We also perform bulk RNAseq analysis on 10 human synchronous DCIS-IDC pairs comprised of estrogen receptor (ER) positive and ER-negative subsets and utilize 2 additional public human DCIS data sets for comparison to our mouse model. By identifying malignant cells using inferred DNA copy number changes from the murine C3Tag scRNAseq data, we show the existence of cancer cells within the C3Tag pre-DCIS, DCIS, and IDC-like tumor specimens. These cancer cells were further classified into proliferative, hypoxic, and inflammatory subpopulations, which change in frequency in DCIS versus IDC. The C3Tag tumor progression model was also associated with increase in Cancer-Associated Fibroblasts and decrease in activated T cells in IDC. Importantly, we translate the C3Tag murine genomic findings into human DCIS where we find common features only with human basal-like DCIS, suggesting there are intrinsic subtype unique DCIS features. This study identifies several tumor and microenvironmental features associated with DCIS progression and may also provide genomic signatures that can identify progression-prone DCIS within the context of human basal-like breast cancers

Infantile Myofibroma Eroding into the Frontal Bone: A Case Report and Review of Its Histopathologic Differential Diagnosis

Infantile myofibroma is a rare and benign tumour of children presenting in the head and neck region. Rendering a final diagnosis of infantile myofibroma can be challenging in the light of nonspecific clinical, radiological findings and its histopathological similarities with a number of neoplasms especially spindle cell tumours. In this paper we discuss a case of infantile myofibroma in a 2-month-old infant, enumerating the various differential entities that have to be eliminated in reaching its specific diagnosis and highlighting the importance of immunopositivity to vimentin and smooth muscle actin (SMA) in establishing its myofibroblastic differentiation

A single-cell and spatially resolved atlas of human breast cancers

Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2+ macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed ‘ecotypes’, with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer