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Aging-associated alterations in mammary epithelia and stroma revealed by single-cell RNA sequencing

ABSTRACT: Aging of the mammary gland is closely associated with increased susceptibility to breast cancer, yet there have been limited systematic studies of aging-induced alterations within this organ. Here we leveraged the power of high-throughput single-cell RNA-sequencing (scRNA-seq) to generate a detailed transcriptomic atlas of young and aged murine mammary tissues, including both epithelial and stromal cell types. This analysis identified altered proportions and distinct gene expression patterns in multiple cell populations as a consequence of aging, independent of history of pregnancy and hormone cycle. In addition, we detected a rare luminal cell type that expresses both hormone-sensing and alveolar lineage markers as well as a unique gene expression signature. In addition, these cells exhibit a significant decrease in relative abundance with age. Overall, this high-resolution transcriptomic landscape reveals the effects of aging on normal mammary gland physiology and can serve as a valuable resource for understanding aging-associated susceptibility to breast cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE150580 | GEO | 2020/12/29

REPOSITORIES: GEO

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Project description:Purpose: Leveraging genome-wide lineage-specific transcriptional profiling of human mammary luminal epithelial cells (LEPs) and myoepithelial cells (MEPs) to elucidate the molecular mechanisms underlying aging-associated breast cancer susceptibility. Methods: Human mammary luminal epithelial and myoepithelial cells were isolated from finite lifespan, non-immortalized human mammary epithelial cells (HMECs) derived from primary breast tissue of women across different age cohorts and breast cancer risk profiles. Transcriptional profiles of LEP and MEP cells were generated via RNA-sequencing performed on Illumina HiSeq 2500. RNA-Seq reads were trimmed using Trimmomatic software, and the processed reads were mapped back to the human genome (hg19) using TOPHAT2. Count matrices were generated using HTSeq. Results: Genome-wide loss of lineage fidelity is a hallmark of aging breast epithelia. Age-dependent differential expression occurred almost exclusively in luminal cells characterized by luminal epithelial cells of older women expressing markers normally expressed in myoepithelial cells. Luminal epithelial cells from histologically normal breast tissue from younger women who carry germline mutations in BRCA1, BRCA2, or PALB2 genes and who are considered to be clinically high risk for breast cancer also exhibited these hallmarks of accelerated aging. Furthermore, accelerated aging of these genetically high risk luminal epithelial cells could be predicted using a biological clock trained on gene expression and DNA methylation profiles of the luminal-specific ELF5 transcription factor. Conclusions: Our study shows that lineage-specific analysis is critical to understanding the molecular mechanisms underlying aging-associated cancer susceptibility. Our results suggest that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. Moreover, breast aging hallmarks identified in our study reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk.

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Aging-associated alterations in mammary epithelia and stroma revealed by single-cell RNA sequencing

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