Abstract 3852: The chemokine C-C motif ligand 2 (CCL2) plays an important role in skeletal muscle wasting associated with breast cancer progression

Abstract

Abstract Up to 45% of breast cancer patients experience a condition called Skeletal Muscle Wasting (SMW). SMW causes significant progressive muscle loss, weakness, and fatigue. SMW in patients adversely affects quality of life during and results in a severely reduced ability of patients to tolerate chemotherapeutic drugs. Chemotherapy itself also exacerbates SMW in patients. There are currently no effective therapies for SMW. This condition is rarely reported in patient records and is often overlooked in patients with a high body mass index. Although this condition is associated with significantly lower survival rates compared to patients with relatively normal muscle mass, we do not yet understand the molecular mechanism by which it occurs in breast cancer patients. In this study, we investigate the role that CCL2 plays in breast cancer and chemotherapy induced SMW. CCL2 is a chemokine that regulates recruitment of immune cells to sites of injury and inflammation. CCL2 is overexpressed in breast cancer and SMW has been linked to elevated levels of CCL2. CCL2 overexpression is also associated with high mortality rates in breast cancer patients. To investigate the role of CCL2 in muscle wasting we treated C2C12 mouse muscle cells with increasing concentrations of CCL2. This led to increased expression of markers of muscle degradation, MuRF-1 and Atrogin-1, with reduced muscle cell proliferation and muscle cell size. This indicates that high levels of CCL2 cause muscle degradation. Using an MDA-MB-231 model of breast cancer, we show that CCL2 knockdown in the primary breast tumor decreases the expression of muscle degradation markers. Further experiments using the 4T1 mammary tumor model show that mice in which CCL2 was knocked down exhibited greater grip strength than those mice in which CCL2 levels remained unaltered. Therefore, CCL2 knockdown reduces muscle degradation and increases grip strength in a mouse model of breast cancer. We also investigated the effect of chemotherapy on SMW. Preliminary in vitro data shows increased expression of CCL2 in response to chemotherapy treatment, while in vivo experiments using the 4T1 breast tumor model indicate that chemotherapeutic treatment also significantly reduces grip strength in mice. Our findings suggest that we can improve patient survival rates and quality of life by developing therapies to combat muscle loss during and after treatment. Understanding the mechanism of muscle wasting is necessary to provide insight into novel, targeted therapeutics to reduce SMW and enhance effectiveness of anti-cancer drugs. Citation Format: Nadia Alissa, Wei Bin Fang, Gage Brummer, Marcela Mitchell, John Thyfault, Paige Geiger, Nikki Cheng. The chemokine C-C motif ligand 2 (CCL2) plays an important role in skeletal muscle wasting associated with breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3852.