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Mammary epithelial cells have lineage-rooted metabolic identities

ABSTRACT: Cancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast cancer is not a disease of a singular origin. Multiple epithelial populations serve as the culprit cell-of-origin for specific breast cancer subtypes, yet our knowledge of the metabolic network of normal mammary epithelial cells is limited. Using a multi-OMIC approach, here we identify the diverse metabolic programs operating in normal mammary populations. The proteomes of basal, luminal progenitor, and mature luminal cell populations revealed enrichment of glycolysis in basal cells and of oxidative phosphorylation in luminal progenitors. Single-cell transcriptomes corroborated lineage-specific metabolic identities and additional intra-lineage heterogeneity. Mitochondrial form-and-function differed across lineages, with clonogenicity correlating to mitochondrial activity. Targeting oxidative phosphorylation and glycolysis with inhibitors exposed lineage-rooted metabolic vulnerabilities of mammary progenitors. Bioinformatics indicated breast cancer subtypes retain metabolic features of their putative cell-of-origin. Thus, lineage-rooted metabolic identities of normal mammary cells may underlie breast cancer metabolic heterogeneity and targeting these vulnerabilities could advance breast cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168660 | GEO | 2021/04/28

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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Mammary epithelial cells have lineage-rooted metabolic identities

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