Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility

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 is a bilayer of two major phenotypically and functionally distinct cell lineages, the luminal epithelial and myoepithelial cells. We have shown that mammary epithelia exhibit substantial stereotypical changes with age which merits attention as they are putative breast cancer cells of origin. We hypothesize that effects from aging that impinge upon maintenance of lineage fidelity increases susceptibility to cancer initiation. From transcriptomic analyses of luminal and myoepithelial lineages from reduction mammoplasties, we identified two models of age-dependent changes in gene expression -- directional changes and increased variance -- that contributed to genome-wide loss of lineage fidelity. Age-dependent variant responses were common to both lineages, whereas directional changes were almost exclusively detected in luminal epithelia and implicated downregulation of chromatin and genome organizers such as SATB1. Epithelial expression of gap junction protein GJB6 increased with age, and modulation of GJB6 expression in heterochronous co-cultures revealed that it provided a communication conduit from myoepithelial cells that drove directional change in luminal cells. Age-dependent luminal transcriptomes comprised a prominent signal detectable in bulk tissue during aging and transition into frank cancers. A luminal-specific aging biomarker machine learning classifier distinguished normal tissue from breast cancers and was predictive of PAM50 breast cancer subtypes. The variability in expression of age-dependent genes across individuals may influence differential susceptibility to breast cancer initiation in a subtype-specific manner. We speculate that luminal epithelia are the ultimate site of integration of the variant responses to aging in their surrounding tissue and that their emergent aging phenotype both endows cells with the ability to become cancer cells of origin and embodies a biosensor that presages cancer susceptibility.

Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer

“…Several DE genes (n=69) in mouse luminal cells were also detected in a recent study of aged human luminal epithelial cells in vitro 67 ( Supplementary Table 3h ). Shared aging patterns between human and mice include the upregulation of: i) Fkbp5 , a regulator of AKT and NFκB pathways, as well as of the androgen–receptor complex, and mostly known for being the target of the drug Rapamycin 68 ; ii) stromal type IV collagen Col4a6 , a protein that is often upregulated in metastatic breast tumors 69 ; iii) Ifi204, an interferon activated protein implicated in DNA repair and STING-mediated type-I interferon production 70 ; iv) Slk , a kinase involved in cell migration downstream of Erbb2 71 ; and downregulation of v) epithelia-specific TF Elf5 , a known marker of luminal aging in humans 72 ; vi) Ntn4 , a regulator of EMT in breast cancer 73 ; v) Tead2 , a TF that belongs to the family of nuclear effectors of the Hippo, TNF, and Wnt pathways 74 .…”

Epigenetic Clocks and Programmatic Aging

“…Epithelial tissue within the breast shows maturo-developmental plasticity that supports lactational function. It was recently reported that over the course of time during adulthood, the methylome of healthy proliferating breast epithelial tissues increasingly resembles that of breast cancer (Sayaman et al, 2022;Senapati et al, 2022). This is a potential example of a maturo-developmental process displaying AP.…”

ELF5: A Molecular Clock for Breast Aging and Cancer Susceptibility

“…SATB1 organizes T cell differentiation [43], epidermis development [44], early postnatal cerebral cortical development [45], and embryonic stem cell differentiation [46]. SATB1 differentially expressed in luminal epithelial cells, and the lineage-specific expression is decreased with age [18]. This raises a potential regulatory mechanism by ELF5 in luminal epithelial cells; ELF5 may interact with SATB1 to orchestrate the regulation of its target genes in the maintenance of luminal epithelial cells and differentiation from luminal progenitors.…”

“…Aging alters breast tissue architecture, with increased adipose cell proportions [11], basement membrane disruption [13], and epithelial composition shifts [14]. Lineage fidelity loss in luminal epithelial cells is a hallmark of aging [14][15][16][17], marked by reduced luminal epithelial cell-specific transcriptomes and methylomes, and the gain of myoepithelial celllike features [17,18]. Although loss of fidelity with age is observed in both lineages, it is most pronounced in luminal epithelial cells.…”