Comparative transcriptomic analysis defines shared and mammary-specific gene expression programs across glandular tissues

The mammary gland is an epithelial secretory organ whose development and differentiation are regulated by hormonal and transcriptional programs. While mammary differentiation has been extensively studied, how mammary gene expression relates to that of other epithelial secretory organs remains incompletely defined. Here, we performed a comparative transcriptomic analysis of human mammary tissue in the context of multiple epithelial secretory and non-glandular tissues using GTEx bulk RNA-seq data. By integrating cross-tissue differential expression analysis with single-cell expression references, co-expression network analysis, and evolutionary comparisons, we aimed to distinguish transcriptional programs that are shared across glandular epithelia from those that are specific to the mammary gland. Our analyses identify three major classes of gene expression programs: glandular-enriched programs shared among epithelial secretory organs, mammary-specific programs associated with metabolic and hormone-responsive functions, and female-biased programs largely linked to immune-related processes. Comparative evolutionary analyses further suggest that mammary specialization predominantly reflects regulatory redeployment of conserved gene modules rather than the emergence of mammalian-specific genes. Together, these findings place mammary gene expression within a broader framework of epithelial secretory biology and support a model in which mammary-specific functions arise through selective reweighting and organization of conserved transcriptional programs. This comparative perspective provides insight into the molecular basis of mammary differentiation and the evolutionary logic underlying specialization of epithelial secretory organs.