Impact of Mitochondrial Dysfunction on Hormone-Responsive Breast Cancer Metastasis

Abstract

Mitochondrial liability is emerging as a central mechanism amplifying the metastasis of hormone-responsive breast cancer, yet the precise roles whereby steroid hormone signaling modifies mtDNA and organelle function are ill-defined. We employed ER+/PR+ highlights (MCF-7, T47D) and pulsatile estradiol and progesterone exposure, quantifying mitochondrial metrics via the Seahorse XF platform (OCR/ECAR), high-resolution confocal 3D reconstruction, and COMSOL Multiphysics finite element modeling for ROS extraction. Hormonal stimulation triggered a distinct bioenergetic reprogramming, manifesting as a 1.8-fold escalation in basal O2 consumption and a 2.1-fold enhancement in glycolytic capacity compared to vehicle (p<0.001). Structural assays identified a 36% contraction of polar mitochondrial branches and increased fission, coinciding with a ROS surge reaching 150% of pluripotent basal levels focalized to the perinuclear mitochondrial cloud. Monte Carlo-derived metastatic timelines predicted that merged bioenergetic and fission metrics elevated the simulated xenograft hazard ratio by 42% over 18 months. Extensive interrogation of hormone-independent datasets confirmed this mitochondrial, structural, and ROS axis is distinctively reprogrammed in metastatic, hormone-dependent disease. Collectively, these integrated multi-scale data authenticate a hormone-dependent mitochondrial reprogramming axis that drives metastatic outgrowth, advocating for mt-targeting strategies in ER+/PR+ breast therapeutics