Background: Metabolic disorders are prevalent in women with breast cancer and breast cancer survivors. Such disorders increase breast cancer mortality and likelihood of relapse 2- and 3-fold, respectively. However, there is a severe lack of research into the physiological sequelae of breast cancer, including the metabolic health consequences. The aim of the present study was to provide
novel insights into the causes of metabolic disturbances associated with breast cancer by investigating the effects of breast cancer on insulin sensitivity in skeletal muscle. Method: L6 myotubes stably expressing GLUT4 were incubated for 72 hours in normal growth medium or medium supplemented with 25% conditioned media (CM) from either MCF7 or BT474 breast cancer cells. Basal and insulin- (100nM) stimulated GLUT4 translocation, 2-deoxyglucose (2DG) uptake, and intracellular insulin signaling was determined in day 7 myotubes.
Results: Basal- and insulin-stimulated GLUT4 translocation was reduced in L6 myotubes incubated with MCF7 (basal: -7%, insulin: -14%, p<0.01) or BT474 (basal: -16%, insulin: -8%, p<0.01) breast cancer CM. Insulin-stimulated 2DG uptake in L6 myotubes was also reduced by MCF7 (-5%, p<0.05) and BT474 (-10%, p<0.05) breast cancer CM. Insulin-stimulated p-Akt^Thr308 (but not pAkt^Ser473) phosphorylation tended to be reduced (-25%, p<0.1) in L6 myotubes incubated with MCF7 or BT474 breast cancer CM, while p-TBC1D4^Thr642 phosphorylation was enhanced (+34%, p<0.05) by MCF7 breast cancer CM.
Conclusion: We conclude that breast cancer reduces muscle insulin responsiveness, evidenced as reduced insulin-stimulated GLUT4 translocation, downregulated glucose uptake, and blunted intracellular insulin sigaling in L6 myotubes incubated with breast cancer cell CM. Thus, skeletal muscle insulin resistance might contribute to metabolic disorders prevalent in women with breast cancer and could be a potential treatment target.