Semester

Fall

Date of Graduation

2021

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Exercise Physiology

Committee Chair

Emidio E. Pistilli

Committee Member

Randall W. Bryner

Committee Member

John M. Hollander

Committee Member

Elena N. Pugacheva

Committee Member

Werner J. Geldenhuys

Abstract

According to the latest statistics from the National Cancer Institute (NCI), about 1 in 8 U.S. women (~13%) will develop invasive breast cancer over the course of their lifetime. This translates to an estimated 268,600 new cases of breast cancer for the year 2019, and these diagnoses will collectively make up 15% of all new cancer cases across all cancer types. The majority of these women will experience the often-debilitating symptom of breast cancer-induced fatigue. these patients often have difficulty performing normal activities of daily living, have decreased tolerance to traditional tumor-directed therapies, and have higher rates of cancer recurrence. Additionally, no effective drug therapies are currently in use for the treatment of breast cancer-induced fatigue. This work aimed to identify molecular changes within the skeletal muscle of a variety of breast cancer models. The downregulation of skeletal muscle peroxisome proliferator activated-receptor gamma (PPARG) was consistently identified within breast cancer models, leading to altered transcriptional networks in pathways that regulate various aspects of metabolic and mitochondrial function. Breast cancer was found to induce mitochondrial oxidative dysfunction and aberrant lipid metabolism within skeletal muscle. These changes were found to be independent of prior treatment status, breast cancer molecular subtype, and weight loss. The identification of weight stable changes in overall skeletal muscle transcriptional and mitochondrial function is a key aspect of this work, and should be used to supplement future diagnostic guidelines and intervention criteria within the field of cancer-associated cachexia. To address this dysfunction, we targeted the transcriptional function of PPARG using the PPAR agonist pioglitazone. We found that 2 weeks of pioglitazone supplementation was able to restore skeletal muscle transcriptional networks and increase both mitochondrial ATP content and ATP synthase activity. This preclinical data was used to serve as rationale and support for a recently approved clinical trial that will examine pioglitazone supplementation in breast cancer patients. Mechanistically, preliminary data suggests that this skeletal muscle transcriptional and mitochondrial dysfunction is caused by tumor-derived factors such as miRNA containing exosomes. Collectively, this work demonstrates that targeting skeletal muscle PPARG transcriptional activity in breast cancer represents a promising therapeutic strategy to improve breast cancer-induced fatigue.

Embargo Reason

Publication Pending

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