Role of DCAF8 in Mammary Ductal Elongation and Branching Morphogenesis.

Postnatal mammary gland development involves the formation of a highly branched epithelial ductal tree, primarily through the elongation and branching morphogenesis of mammary epithelial ducts. Multiple factors are involved in this process, in which both estrogen and progesterone receptors (ER/PR) play a crucial role. In this study, we identified a role of DCAF8 in promoting mammary ductal elongation and branching through its impacts on ER/PR signaling. Homozygous Dcaf8 knockout mice exhibited significant delay in mammary ductal elongation during puberty, which was characterized by a reduction in mammary ductal elongation area and distance, and terminal end buds (TEBs); abnormal branching morphogenesis of mammary ducts was also observed in adult Dcaf8 null mice, which was characterized by a reduction of lateral branches and an increase of ductal bifurcation. To further elucidate the mechanism underlying DCAF8’s role in mouse mammary development, we performed transcriptomic sequencing and biochemical experiments. The results revealed that downstream key effectors of the PR signaling pathway were significantly downregulated, while the expression of ERβ, a potential inhibitor of ERα/PR signaling, was significantly elevated in the mammary gland of Dcaf8 null mice. Collectively, this study suggests that DCAF8 may play an important role in mammary development by promoting ductal elongation and branching morphogenesis, through ERβ-mediated inhibition of ERα/PR signaling pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10911-026-09604-z.