DRP1-mediated mitochondrial fission integrates growth hormone signaling with metabolic and stress adaptation in triple-negative breast cancer

Triple-negative breast cancer (TNBC) relies on metabolic plasticity to sustain growth under diverse microenvironmental conditions. Although growth hormone (GH) signaling has been linked to breast cancer progression, its mechanistic integration with mitochondrial dynamics and metabolic reprogramming remains unclear. Here, we show that GH promotes TNBC progression accompanied by DRP1-associated mitochondrial remodeling, as indicated by sensitivity to Mdivi-1. The MDA-MB-231 line enabled integrated assessment across 2D, 3D, hypoxia, and in vivo xenografts using consistent workflows and readouts. GH increased proliferation and mitochondrial mass without increasing OCR under protein normalization. Instead, GH selectively enhanced glycolytic flux and metabolic flexibility. Inhibition of DRP1 uncoupled GH-induced glycolysis from proliferation, demonstrating that mitochondrial fission is required to link metabolic reprogramming to cell-cycle progression. DRP1 inhibition with Mdivi-1 was associated with altered TP53 and HIF1A expression and extended GH activity to the regulation of a pro-inflammatory tumor microenvironment marked by cxcr4b, il8, and il12. Consistent with these findings, analysis of human TNBC transcriptomes revealed conserved enrichment of mitochondrial, metabolic, and inflammatory pathways. Together, these results support the GH-DRP1 axis as a candidate regulator of mitochondrial dynamics, metabolic plasticity, tumor progression and tumor microenvironment interactions in TNBC.