Age-related gene expression in luminal epithelial cells is driven by a microenvironment made from myoepithelial cells

Research output: Contribution to journalArticle

Authors

  • Masaru Miyano
  • Rosalyn W Sayaman
  • Marcus H Stoiber
  • Chun-Han Lin
  • Martha R Stampfer
  • Mark A LaBarge

Colleges, School and Institutes

External organisations

  • Department of Population Sciences, City of Hope, Duarte, CA, 91010, USA.
  • Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Mailstop 977, Berkeley, California 94720, USA.
  • Envrionmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  • Department of Environmental Bioinformatics, University of Birmingham, Birmingham, UK.
  • Center for Cancer Biomarkers Research, University of Bergen, Bergen, Norway.

Abstract

Luminal epithelial cells in the breast gradually alter gene and protein expression with age, appearing to lose lineage-specificity by acquiring myoepithelial-like characteristics. We hypothesize that the luminal lineage is particularly sensitive to microenvironment changes, and age-related microenvironment changes cause altered luminal cell phenotypes. To evaluate the effects of different microenvironments on the fidelity of epigenetically regulated luminal and myoepithelial gene expression, we generated a set of lineage-specific probes for genes that are controlled through DNA methylation. Culturing primary luminal cells under conditions that favor myoepithelial propogation led to their reprogramming at the level of gene methylation, and to a more myoepithelial-like expression profile. Primary luminal cells' lineage-specific gene expression could be maintained when they were cultured as bilayers with primary myoepithelial cells. Isogenic stromal fibroblast co-cultures were unable to maintain the luminal phenotype. Mixed-age luminal-myoepithelial bilayers revealed that luminal cells adopt transcription and methylation patterns consistent with the chronological age of the myoepithelial cells. We provide evidence that the luminal epithelial phenotype is exquisitely sensitive to microenvironment conditions, and that states of aging are cell non-autonomously communicated through microenvironment cues over at least one cell diameter.

Details

Original languageEnglish
Pages (from-to)2026-2051
Number of pages26
JournalAging
Volume9
Issue number10
Publication statusPublished - 9 Oct 2017

Keywords

  • Aging, Breast/cytology, Cell Lineage, Cellular Microenvironment, Coculture Techniques, Epithelial Cells/cytology, Female, Humans, Phenotype, Transcriptome