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.
Highlights
The incidence of most carcinomas increases with age; more than 80% of breast cancers are diagnosed in women over 50, but the biology underlying this striking consequence of aging is not understood
These genes showed lineage-specific expression (Fig. 1B) that was inversely correlated with promoter DNA methylation (Fig. 1C) in luminal epithelial cells (LEP) and myoepithelial cells (MEP) from eight different women
Intrinsic changes that occur in MEP during aging can exert aging phenotypes on neighboring LEP by altering gene expression networks, revealing the possibility that aging LEP phenotypes occur through a cell non-autonomous mechanism
Summary
The incidence of most carcinomas increases with age; more than 80% of breast cancers are diagnosed in women over 50, but the biology underlying this striking consequence of aging is not understood. Aging in the breast stroma is characterized by prominent microenvironment changes such as increased fat content and decreased connective tissue [2, 3]. In the epithelia, aging is accompanied by increases www.aging‐us.com in estrogen receptor expression [4], decreased proportions of tumor suppressive MEP, accumulation of dysfunctional multipotent progenitors, and acquisition by LEP of biochemical and molecular properties normally observed only in MEP of younger women (e.g. expression of keratin 14, YAP, TAZ, and integrin alpha 6, and decreased expression of keratin 19) [5, 6]. An understanding of how LEP-MEP interactions may regulate LEP lineage fidelity, and its loss and dysregulation with age, may elucidate the mechanism behind increased breast cancer susceptibility with age
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