Semester

Summer

Date of Graduation

2020

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

Lori Hazlehurst

Committee Member

Wei Du

Committee Member

John Hollander

Committee Member

Malcolm Mattes

Committee Member

Elena Pugacheva

Abstract

Women diagnosed with breast cancer (BC) currently represent the largest group of cancer survivors in the United States, accounting for over 20% of those living after a cancer diagnosis. Most BC survivors report an unusual degree of fatigue, which can present prior to diagnosis and continue for many years after treatment cessation. Recent studies show that deficits in muscle function predict shorter survival in cancer, perhaps due to the fact that fatigue is known to reduce a patient’s tolerance to anti-cancer therapies. Therefore, improving muscle function in BC patients has the potential to improve both quality of life and survival in the most commonly diagnosed cancer type. At present, few therapies for cancer-related fatigue show clinical efficacy, and the pathogenesis of this condition is largely unknown. This work aimed to identify molecular changes induced in skeletal muscle by BC, using patient samples and by developing novel in vitro and in vivo model systems. We tested the hypothesis that BC induces dysregulation of metabolic pathways regardless of molecular subtype or treatment history. Transcriptomic and proteomic analyses in BC patient muscle samples indicated mitochondrial dysf­unction, which was evident across all molecular subtypes of BC and unrelated to patients’ treatment histories. In vitro and in vivo experimentation confirmed the ability of BC cells to alter mitochondrial respiration and ATP content in muscle tissue via a secreted factor without the involvement of immune or stromal cell mediators. These data indicate that BC-induced fatigue is related to defects in skeletal muscle mitochondrial function induced directly by BC cells, and that targeting mitochondrial function or mitochondrial density in muscle could be a viable therapeutic strategy to improve both survival and quality of life in BC survivors.

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