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Age associated epigenome changes in human mammary epithelial cells (ATAC-Seq)

ABSTRACT: ATAC-seq profiling of luminal epithelial cells obtained from reduction mammoplasty tissue from young (<30 year) and old (>55 year) individuals.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158879 | GEO | 2023/06/09

REPOSITORIES: GEO

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Project description:Age and physiological status like menopause are key factors in mammary development and are associated with breast cancer risk. Less clear is what factors influence breast cancer intrinsic subtypes that are associated with prognosis. Here, we investigated the age of the host in a mammary chimera model. The mammary glands of wildtype BALB/c mice were cleared of endogenous epithelium at 3 weeks of age and subsequently transplanted during puberty (5 weeks) or upon maturation (10 weeks) with syngeneic Trp53null mammary fragments. The Trp53null mammary epithelium undergoes a high rate of neoplastic transformation, such that carcinomas arise over the course of a year. Tumors arose more rapidly (p=0.003, log-rank test) when transplanted to adult hosts (AH, n=89) compared to tumors arising following transplantation into juvenile hosts (JH, n=55). However, JH tumors grew several times faster than AH tumors, were more perfused as indicated by 2-fold larger blood vessels (p=0.015), and exhibited a 2-fold higher mitotic index (p=0.009). Transplantation into juvenile hosts (JH) gave rise to 80% ER positive tumors compared to 60% in adult hosts. However, tumor cells were significantly more ER immunoreactive (p=0.0001) in JH tumors compared to those in AH tumors and were more highly positive for insulin like growth factor receptor phosphorylation (p=0.026). Expression profiles of JH (n=15) and AH (n=12) tumors identified 243 differentially expressed genes. The main biological processes enriched in JH tumors were organ morphology, proliferation, and lipid metabolism. An expression profile of juvenile versus adult (JVA) tumors revealed a luminal transcriptional program, characterized by expression of Foxa1, Igf2, Ccnd1 and Fgfr2. The human homologs of JVA genes (JVAh) were used to create two centroids (AHh or JHh) to classify human breast cancers from archival microarray datasets in two-dimensional space. Luminal human breast cancers were more like JH tumors compared to basal-like cancers, whereas luminal A tumors were more like JH tumors than luminal B tumors. Consistent with this, JVAh genes segregated human luminal A from luminal B breast cancers via hierarchical clustering. The distinct biology of tumors arising from tissue undergoing morphogenesis in the context of puberty suggests that young age at neoplastic transformation promotes a luminal tumor phenotype and supports the contention that the tumor intrinsic subtype is influenced by physiological status at the time of putative initiation.

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Age associated epigenome changes in human mammary epithelial cells (ATAC-Seq)

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