Dysregulation of metabolic‐associated pathways in muscle of breast cancer patients: preclinical evaluation of interleukin‐15 targeting fatigue

Abstract

BackgroundBreast cancer patients report a perception of increased muscle fatigue, which can persist following surgery and standardized therapies. In a clinical experiment, we tested the hypothesis that pathways regulating skeletal muscle fatigue are down‐regulated in skeletal muscle of breast cancer patients and that different muscle gene expression patterns exist between breast tumour subtypes. In a preclinical study, we tested the hypothesis that mammary tumour growth in mice induces skeletal muscle fatigue and that overexpression of the cytokine interleukin‐15 (IL‐15) can attenuate mammary tumour‐induced muscle fatigue.MethodsEarly stage non‐metastatic female breast cancer patients (n = 14) and female non‐cancer patients (n = 6) provided a muscle biopsy of the pectoralis major muscle during mastectomy, lumpectomy, or breast reconstruction surgeries. The breast cancer patients were diagnosed with either luminal (ER+/PR+, n = 6), triple positive (ER+/PR+/Her2/neu+, n = 5), or triple negative (ER−/PR−/Her2/neu−, n = 3) breast tumours and were being treated with curative intent either with neoadjuvant chemotherapy followed by surgery or surgery followed by standard post‐operative therapy. Biopsies were used for RNA‐sequencing to compare the skeletal muscle gene expression patterns between breast cancer patients and non‐cancer patients. The C57BL/6 mouse syngeneic mammary tumour cell line, E0771, was used to induce mammary tumours in immunocompetent mice, and isometric muscle contractile properties and fatigue properties were analysed following 4 weeks of tumour growth.ResultsRNA‐sequencing and subsequent bioinformatics analyses revealed a dysregulation of canonical pathways involved in oxidative phosphorylation, mitochondrial dysfunction, peroxisome proliferator‐activated receptor signalling and activation, and IL‐15 signalling and production. In a preclinical mouse model of breast cancer, the rate of muscle fatigue was greater in mice exposed to mammary tumour growth for 4 weeks, and this greater muscle fatigue was attenuated in transgenic mice that overexpressed the cytokine IL‐15.ConclusionsOur data identify novel genes and pathways dysregulated in the muscles of breast cancer patients with early stage non‐metastatic disease, with particularly aberrant expression among genes that would predispose these patients to greater muscle fatigue. Furthermore, we demonstrate that IL‐15 overexpression can attenuate muscle fatigue associated with mammary tumour growth in a preclinical mouse model of breast cancer. Therefore, we propose that skeletal muscle fatigue is an inherent consequence of breast tumour growth, and this greater fatigue can be targeted therapeutically.

Breast cancer-associated skeletal muscle mitochondrial dysfunction and lipid accumulation is reversed by PPARG

“…These results provide support for previous publications implicating the PPAR proteins in BC-induced skeletal muscle fatigue and provide rationale for investigating PPAR agonists to improve quality of life in survivors of BC (20,46). and 5% β-mercaptoethanol.…”

Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype

“…This indicates that the ERPR, TP, and TN groups share a greater number of DEGs in skeletal muscle than one would expect if the DEGs were independent of subtype and in contrast, muscle from HER2 patients does not exhibit the same similarity to the other subtypes in terms of shared DEGs ( Figure 3C). Collectively, these data demonstrate that transcriptional responses in skeletal muscle of patients with ERPR, TP and TN tumors are highly similar, in support of previous data from our laboratory 14,15 . Furthermore, the transcriptional responses in muscles from patients with HER2/neu-overexpressing tumors partially overlap with the other subtypes, but exhibit a significant contrast to the other 3 subtypes, suggesting that this tumor type is associated with a unique transcriptional adaptation within skeletal muscle.…”

“…When the 43 overlapping pathways were ranked by how similarly all subtypes appeared in terms of magnitude and directionality of dysregulation, LXR/RXR signaling stood out in its strong, consistent inhibition across all BC subtypes ( Figure 4D), and the related TR/RXR pathway was also identified as consistently significantly dysregulated. These pathways are closely related to and often integrated with the PPAR/RXR signaling pathway, which our laboratory has previously identified as a likely upstream regulator of muscle fatigue in BC patients 14,15 .…”

“…Our laboratory has recently reported that skeletal muscle of women with BC exhibits a distinct gene expression signature that is not dependent on molecular subtype 14 . Furthermore, we have identified signaling via the metabolic regulators of the peroxisome-proliferator activated 5 receptor (PPAR) family as potential key mediators of fatigue in women with BC and female mice bearing BC patient-derived orthotopic xenografts (PDOXs) 15 .…”

Recent advances in cardio‐oncology: a report from the ‘Heart Failure Association 2019 and World Congress on Acute Heart Failure 2019’

“…2 These patients often suffer from multiple different co-morbidities that may develop as consequences from anti-cancer therapies. Frequent problems include, but are not limited to, chronic kidney disease, 3,4 liver dysfunction, 5,6 gastrointestinal disease, 7,8 anaemia, 9,10 fatigue, 11,12 infections, 13,14 anorexia 15,16 , muscle wasting, 17,18 pain, 19,20 and heart failure (HF). 21,22 Depending on the cancer diagnosis and the type of anti-cancer treatment, cardiotoxicity rates may vary from 0% to 48% of patients, with HF being a predominant presentation.…”