Abstract Body: Introduction: Exercise is an effective way for reducing breast cancer-induced cardiac injury to a certain extent. However, the underlying mechanism remain unclear.
Research Questions: Whether voluntary exercise (VE) activated cardiac signal transducer and activator of transcription 3 (STAT3) to protect against breast cancer-induced cardiac injury.
Goals: To study the role of STAT3 in VE against breast cancer-induced cardiac injury.
Methods: STAT3 tyrosine 705 phosphorylation and cardiac function were evaluated in the cardiomyocytes of transgenic breast cancer female mice [mouse mammary tumor virus–polyomavirus middle T antigen (MMTV-PyMT+)] and littermate mice with no cancer (MMTV-PyMT−) with or without VE for 4 weeks. Masson’s trichrome staining and wheat germ agglutinin staining were done for histological detection. MicroRNA (miRNA) sequencing was used to identify the key miRNAs mediating the effects of VE on breast cancer-induced cardiac injury. Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutation (AAVmu) were used to interfere with the activation of STAT3 in vivo. Isolated cardiomyocytes and AC16 cells were used to investigate the regulation of miRNA through VE-activated STAT3 in vitro.
Results: VE for 4 weeks not only improve the cardiac function of MMTV-PyMT+ mice compared with littermate mice with MMTV-PyMT− mice, but also increase myocardial STAT3 tyrosine 705 phosphorylation. The histological analysis showed more obvious cardiac fibrosis and smaller cardiomyocytes size in MMTV-PyMT+ mice compared with MMTV-PyMT− mice and VE could ameliorate them. MicroRNA (miRNA) sequencing identified that miR-181a was up-regulated and miR-130b was down-regulated, contributing to the modulation of VE induced-cardioprotection. Myocardial injection of AAVmu abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a, which was the precursor of miR-181a and HOTAIR (HOX transcript antisense RNA), which sponged miR-130b. Furthermore, miR-181a targeting PTEN and miR-130b targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved.
Conclusions: Voluntary exercise protects against breast cancer-induced cardiac injury via activating STAT3. Activated STAT3 promotes miR-181a expression targeting PTEN and promotes HOTAIR to sponge miR-130b targeting Zbtb20. These findings help to develop new target in exercise therapy for breast cancer-induced cardiac injury.