Abstract PR006: Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility
Authors: Miyano Masaru , Sayaman Rosalyn W. , Senapati Parijat , Hinz Stefan , Seewaldt Victoria E. , Schones Dustin , LaBarge Mark A. 
Published: January 2023

Abstract
Effects from aging in any single cell are unpredictable, whereas aging phenotypes at the organ and tissue levels tend to appear as stereotypical changes. The mammary epithelium, the origin of breast carcinomas, is a bilayer of two major phenotypically and functionally distinct cell lineages, the luminal epithelial and myoepithelial cells. We have shown that luminal epithelia exhibit substantial stereotypical changes with age, which merits attention as they are putative breast cancer cells of origin. Hallmark aging changes in mammary gland are loss of lineage specificity in luminal epithelia exemplified by acquiring expression of proteins normally reserved for myoepithelial cells, and progenitor cells that accumulate and attain a basal differentiation bias. We hypothesize that effects from aging that impinge upon maintenance of lineage specificity increases susceptibility to cancer initiation. Indeed, histologically normal breast tissue from young women, who were known to be highly susceptible to breast cancer because they harbor a germline mutation in BRCA1, BRCA2, or PALB2 genes, exhibited hallmarks of accelerated aging. These included increased proportions of luminal epithelial cells with acquired myoepithelial proteins, acceleration of a breast specific biological clock by 10 to 40 years compared to chronological age, and a basal differentiation bias or failure of differentiation of cKit+ progenitors. To gain insight into the underlying molecular changes we interrogated transcriptomes, proteomes, and methylomes of mammary epithelia at lineage resolution. Strikingly, age-dependent differential gene expression and DNA methylation occurred almost exclusively in luminal epithelia, whereas changes due to increased variance of gene and protein expression occurs in both luminal and myoepithelial lineages. Most gene changes that were previously associated with early breast cancer are detectable as age-driven changes in normal luminal epithelia. The genes with age-dependent differential and variant changes in expression distinguish normal tissue from breast cancers and are predictive of PAM50 breast cancer subtypes. Heterochronus, multilineage, co-cultures demonstrated that the age-dependent phenotype of luminal cells is at least partly dependent on the microenvironment created on the apical surfaces of neighboring myoepithelial cells. We show that increased variance is a substantial outcome of aging and is likely central to understanding increased susceptibility to breast cancer with age. We speculate that the luminal epithelium is a site of integration of the variant responses to aging in their surrounding tissue, and that their emergent phenotype of aging both endows cells with the ability to become a cancer cell of origin and embodies a biosensor that presages one’s cancer susceptibility.
Citation Format: Masaru Miyano, Rosalyn W. Sayaman, Parijat Senapati, Stefan Hinz, Victoria E. Seewaldt, Dustin Schones, Mark A. LaBarge. Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR006.