Comparative Transcriptomics of Human Breast Tissue Suggests Conserved Epithelial Secretory Programs and Tissue-Associated Regulatory Specialization

Abstract The mammary gland represents a defining evolutionary innovation of mammals, which is an epithelial tissue with specialized secretory functions that are regulated by hormonal and transcriptional processes. While mammary differentiation has been extensively studied, its transcriptional relationship to other epithelial tissues with secretory activity has been less explored in an evolutionary context. Here, we used bulk RNA-seq data from the GTEx project to examine gene expression patterns in human breast tissue alongside a set of other tissues that contain epithelial secretory components, as well as non-glandular tissues. Using cross-tissue differential expression analyses, co-expression network analysis, and integration with single-cell expression references, we characterized patterns of gene expression that recur across multiple secretory tissues and those that show relative enrichment in breast tissue. This analysis highlights three broad classes of expression patterns: genes with elevated expression across several secretory tissues, genes showing preferential expression in breast tissue, and genes displaying sex-associated differences in breast samples. These gene sets are associated with distinct functional annotations, including epithelial structure, metabolic and hormone-responsive processes, and immune-related functions. Comparative analyses of gene conservation indicate that many genes preferentially expressed in breast tissue are evolutionarily conserved across vertebrates, consistent with the reuse of pre-existing gene repertoires in the mammalian lineage in tissue-specific contexts. Together, these results support a model in which breast tissue identity reflects the regulatory re-weighting and integration of conserved epithelial secretory modules rather than lineage-specific gene innovation. By placing human breast tissue gene expression in a comparative and evolutionary context, this study provides a molecular framework for understanding how complex organ-level traits arise through regulatory modularity. Significance The mammary gland is a defining feature of mammals, yet it remains unclear how its gene activity relates to that of other tissues with similar secretory functions. By comparing gene expression in human breast tissue with other epithelial secretory tissues, this study shows that much of breast tissue gene expression is shared with a common epithelial program, while a smaller set of genes is associated with breast-specific metabolic and hormonal functions. These findings help clarify how mammary gland specialization arises in mammalian lineages from ancestral genetic materials rather than from entirely new gene emergences, providing a framework for understanding the evolution of new organs.