Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data of pre-stasis cultured HMEC

ABSTRACT: We have generated a large collection of normal human mammary epithelial cell strains from women aged 16 to 91 years, derived from primary tissues, to enable functional and molecular interrogation of aging. We demonstrate in finite-lifespan cultured and uncultured epithelial cells that aging is associated with reduction of myoepithelial cells and with increases in luminal cells expressing keratin 14 and integrin Î±6, traits that are expressed exclusively in myoepithelial cells in women under 30. We find that changes to the luminal lineage result from age-dependent expansion of multipotent progenitors that bear defects resulting in incompletely differentiated luminal cells. These findings were verified in vivo in normal breast tissues. Myoepithelial cells have been suggested to act as tumor suppressors, and progenitor cells are implicated as the etiological roots of mammary carcinomas. Thus with aging there is a shift in the balance of luminal/myoepithelial lineages, and changes in the functional spectrum of multipotent progenitors, which presages increased potential for malignant transformation. Finite lifespan pre-stasis HMEC from specimens from reduction mammoplasties of 7 patients of different age were collected. The expression data was queried for different biological replicates and at different passages. For strain 240, luminal and myoepithelial cells were collected using flow cytometry.

ORGANISM(S): Homo sapiens

SUBMITTER: Francois Pepin

PROVIDER: E-GEOD-37485 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Accumulation of multipotent progenitors with a basal differentiation bias during aging of human mammary epithelia.

Garbe James C JC Pepin Francois F Pelissier Fanny A FA Sputova Klara K Fridriksdottir Agla J AJ Guo Diana E DE Villadsen Rene R Park Morag M Petersen Ole W OW Borowsky Alexander D AD Stampfer Martha R MR Labarge Mark A MA

Cancer research 20120502 14

Women older than 50 years account for 75% of new breast cancer diagnoses, and the majority of these tumors are of a luminal subtype. Although age-associated changes, including endocrine profiles and alterations within the breast microenvironment, increase cancer risk, an understanding of the cellular and molecular mechanisms that underlies these observations is lacking. In this study, we generated a large collection of normal human mammary epithelial cell strains from women ages 16 to 91 years, ...[more]

PMID: 22552289

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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.

Dataset Information

Expression data of pre-stasis cultured HMEC

Publications

Accumulation of multipotent progenitors with a basal differentiation bias during aging of human mammary epithelia.

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