Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype

Abstract

Increased susceptibility to fatigue is a negative predictor of survival commonly experienced by women with breast cancer. Here, we sought to identify molecular changes induced in human skeletal muscle by BC regardless of treatment history or tumor molecular subtype using RNA-sequencing and proteomic analyses. Mitochondrial dysfunction was apparent across all molecular subtypes, with the greatest degree of transcriptomic changes occurring in women with HER2/neu-overexpressing tumors, though muscle from patients of all subtypes exhibited similar pathway-level dysregulation. Interestingly, we found no relationship between anti-cancer treatments and muscle gene expression, suggesting that fatigue is a product of BC per se rather than clinical history. In vitro and in vivo experimentation confirmed the ability of BC cells to alter mitochondrial function and ATP content in muscle. These data suggest that interventions supporting muscle in the presence of BC-induced mitochondrial dysfunction may alleviate fatigue and improve the lives of women with BC.

Breast cancer-secreted factors induce atrophy and reduce basal and insulin-stimulated glucose uptake by inhibiting Rac1 activation in rat myotubes

“…Thus, our present in vitro findings align with in vivo results from humans showing significant molecular rewiring of skeletal muscle in patients with breast cancer. Our study provides mechanistic evidence that might explain why women who develop breast cancer have a higher incidence of metabolic dysfunctions, such as for example diabetes, than women who do not develop breast cancer [39, 40]. Other cancer cell types might also induce muscle insulin resistance, as other cancers have been associated with impaired metabolic regulation.…”

“…That breast cancer rewires the muscles and fat, is supported by a preliminary study revealing that skeletal muscles of women with newly diagnosed breast cancer undergo significant molecular changes. Of these, the most significant changes were precisely for proteins involved in metabolic regulation [39], although no functional outcome of these changes were investigated. Thus, our present in vitro findings align with in vivo results from humans showing significant molecular rewiring of skeletal muscle in patients with breast cancer.…”