Introduction: Tumor growth and neoadjuvant treatment induce a degradation of muscle mass and aerobic fitness in women with breast cancer. These damages can increase toxicity and decrease the effect of chemotherapy. It is also known that the tumor consumes large amounts of glucose due to its glycolytic metabolism. Additionally, aggressively growing tumors are always characterized by increased expression of glucose transporters such as GLUT-1 and, especially in breast tumors, it has been shown that there is a correlation between this transporter expression and proteins related to cell proliferation (Ki-67). For this reason, the tumor can cause insulin resistance, in order to direct a greater amount of glucose for its consumption and increase its proliferation. Since combined training (CT) can decrease the amount of circulating glucose, it is possible to suggest that this decrease will alter the tumor's metabolism, making it less able to consume glucose and, therefore, decreasing its proliferation. Another mechanism that may contribute to reducing tumor aggressiveness is the expression of miRNAs in the bloodstream (c-miRNA) after physical training. It has been shown that c-miRNAs can play an important regulatory role in controlling the expression of tumor suppressor genes, as well as modulating processes that control the expression of oncogenes. Thus, it is possible to suggest that c-miRNAs are some of the main exercines involved in the production of intrinsic effects produced by physical exercise on the tumor. Objectives: To determine the effect of combined training, performed before treatment, on Ki-67 levels in the tumor and on baseline levels and the acute response to exercise on the expression of c-miRNAs in women with breast cancer. Methods: Assuming a sampling error of at most 10%, with a confidence interval equal to 95%, a minimum sample of 100 cases will be required. Thus, 100 women with breast cancer with indication for neoadjuvant chemotherapy will be allocated in one of the following groups: CT before chemotherapy (CT, n=50), or control group (GC, n=50). Then, these women will undergo, both before and after the CT period, the following assessments: 1) body composition by dual-energy X-ray absorptiometry (DXA); 2) muscular strength through the one repetition maximum test (1-RM); 3) aerobic fitness through the direct test of maximum oxygen consumption (VO2max); 4) functionality through the sit and stand and Timed Up and Go tests; 05) quality of life through the FACT-B questionnaire; 6) nutritional intake through food recalls; 7) blood and tumor collections for molecular analyses. Blood samples for molecular analyzes will be collected in 5 moments: 1st) before the first CT session; 2nd) immediately after the first CT session; 3rd) before the last CT session; 4th) immediately after the last CT session; 5th) 3 days after the 8 weeks of CT. CT will be performed 3 times a week. The CT protocol will consist of strength training (8 exercises, 1-3 sets of 8-12 RM at 80-90% of 1-RM and 2 min between sets) followed by aerobic training (3-4 sets of 3 min at 90% of VO2max for 3 min of active recovery (30% of VO2max) on the cycle ergometer. Expected outcomes: If the hypotheses of this project are confirmed, CT performed before treatment will modify the pattern of acute and basal expression of c-miRNAs inserted in extracellular vesicles, in order to induce an increase in the expression of c-miRNAs related to suppression as well as the decrease in the expression of c-miRNAs related to increased tumor progression.
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