bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Ноя. 3, 2024
Abstract Purpose Aromatase Inhibitors (AI) are standard therapy for hormone receptor positive breast cancers in post-menopausal patients. Disease recurrence is common and previous studies suggest that the altered steroid environment may be a driver of resistance. Using label-free mass-spectrometry we explored unique androgen (AR) interactome supervenes AI resistant cancer associated hyperandrogenic environment. Experimental Design AR expression was evaluated primary tissue-microarray (n=875) with nuclear cytoplasmic localization quantified. Liquid-chromatography tandem (LC-MS/MS) analysis utilized to identify proteins interacting models AI-resistance. Validation carried out by co-immunoprecipitation co-localisation studies. Live-cell imaging, Seahorse MitoStress Assays flow cytometry were used quantify changes mitochondria cell metabolism arising Results Utilising digital pathology detected abundant protein poor survival only cohort, most significantly, therapy-refractory Luminal B subtype (p=0.0085). Models AI-resistance excess highlight diffuse localisation throughout cytoplasm nucleus accompanied increased mitochondrial mass membrane potential, oxidative phosphorylation glycolysis. Exploration identified G3BP1, SLIRP, IGFBP5 as partners which stress, adaptive metabolic response estrogen repression. Conclusions The findings this study prognostic potential immunoreactivity specific subtypes uncover novel extra-nuclear interactions mediate adaptations during development endocrine-resistance.
Язык: Английский