A Human Breast Cell Atlas Mapping the Homeostatic Cellular Shifts in the Adult Breast

Abstract

One of the barriers for breast cancer prevention and treatment is our poor understanding of the dynamic cellular shifts that naturally occur within the breast and how these changes contribute to tumour initiation. In this study we report the use of single cell RNA sequencing (scRNAseq) to compile a Human Breast Cell Atlas (HBCA) assembled from 55 donors that had undergone reduction mammoplasties or risk reduction mammoplasties. The data from more than 800,000 cells identified 41 cell subclusters distributed across the epithelial, immune, and stromal compartments. We found that the contribution of these different clusters varied according to the natural history of the tissue. Breast cancer risk modulating factors such as age, parity, and germline mutation affected the homeostatic cellular state of the breast in different ways however, none of the changes observed were restricted to any one cell type. Remarkably, we also found that immune cells from BRCA1/2 carriers had a distinct gene expression signature indicative of potential immune exhaustion. This suggests that immune escape mechanisms could manifest in non-cancerous tissues during very early stages of tumour initiation. Therefore, the Atlas presented here provides the research community with a rich resource that can be used as a reference for studies on the origins of breast cancer which could inform novel approaches for early detection and prevention.

Single nuclei chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry

“…Epithelial cell types were annotated using CD49f/EpCAM markers as done previously into mature luminal (ML), luminal progenitors (LP) and basal cells 11 . These cell clusters have been described with various names in the literature 7,8,12 . In a recent breast cell annotation event organized by Chan-Zuckerberg Initiative that included several research groups involved in developing single cell atlas of the breast, the following terminologies were suggested: luminal hormone sensing (LHS), luminal adaptive secretory precursor cells (LASP) and basal-myoepithelial (BM) cells for mature luminal, luminal progenitor, and basal cells, respectively.…”

“…Murrow et al characterized premenopausal breast tissue at the single cell level to determine coordinated transcriptional programs that alter in response to changing hormonal levels 9 . Two other single cell studies using reduction mammoplasty samples identified three major epithelial cell types in the breast 10,12 . However, there remains a lack of information in differences in cell state based on genetic ancestry and relationship between cell state as defined by transcriptome and chromatin accessibility status.…”

Navigating the manifold of single-cell gene coexpression to discover interpretable gene programs

“…2A). This held true on datasets from diverse organ systems and origins: Human Lung Cell Atlas (2.3 million cells [18]), the 1 million cell survey of embryonic development from Cao et al [19], the Human Breast Cell Atlas (800,000 cells [20]), and the DCM/ACM Heart Cell Atlas (881,000 cells [21]).…”

FABP7 Progenitors are a Targetable Metabolic Root in theBRCA1Breast

“…The breast biology field has invested greatly in dissecting human breast heterogeneity with over 1 million single cells across 200 human breast tissues profiled by scRNAseq to date 2,4,7,8,32 .…”