American Association for Cancer Research
10780432ccr181565-sup-202119_2_supp_5199424_pjmww7.pdf (1.14 MB)

Figure S3 from Human Breast Cancer Xenograft Model Implicates Peroxisome Proliferator–activated Receptor Signaling as Driver of Cancer-induced Muscle Fatigue

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journal contribution
posted on 2023-03-31, 21:28 authored by Hannah E. Wilson, Kacey K. Rhodes, Daniel Rodriguez, Ikttesh Chahal, David A. Stanton, Joseph Bohlen, Mary Davis, Aniello M. Infante, Hannah Hazard-Jenkins, David J. Klinke, Elena N. Pugacheva, Emidio E. Pistilli

Figure S3 shows muscle fatigue and twitch properties of EDL muscles form E0771 tumor bearing mice.



American Cancer Society

National Institute of General Medical Sciences





This study tested the hypothesis that a patient-derived orthotopic xenograft (PDOX) model would recapitulate the common clinical phenomenon of breast cancer–induced skeletal muscle (SkM) fatigue in the absence of muscle wasting. This study additionally sought to identify drivers of this condition to facilitate the development of therapeutic agents for patients with breast cancer experiencing muscle fatigue. Eight female BC-PDOX–bearing mice were produced via transplantation of tumor tissue from 8 female patients with breast cancer. Individual hind limb muscles from BC-PDOX mice were isolated at euthanasia for RNA-sequencing, gene and protein analyses, and an ex vivo muscle contraction protocol to quantify tumor-induced aberrations in SkM function. Differentially expressed genes (DEG) in the BC-PDOX mice relative to control mice were identified using DESeq2, and multiple bioinformatics platforms were employed to contextualize the DEGs. We found that SkM from BC-PDOX–bearing mice showed greater fatigability than control mice, despite no differences in absolute muscle mass. PPAR, mTOR, IL6, IL1, and several other signaling pathways were implicated in the transcriptional changes observed in the BC-PDOX SkM. Moreover, 3 independent in silico analyses identified PPAR signaling as highly dysregulated in the SkM of both BC-PDOX–bearing mice and human patients with early-stage nonmetastatic breast cancer. Collectively, these data demonstrate that the BC-PDOX model recapitulates the expected breast cancer–induced SkM fatigue and further identify aberrant PPAR signaling as an integral factor in the pathology of this condition.

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