# Unraveling the Associations of Molecular-Genetic Bioenergetics and Chemotherapy-Induced Fatigue Symptoms in Patients with Breast Cancer

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $241,500

## Abstract

PROJECT SUMMARY/ABSTRACT
 Cancer-related fatigue (CRF) occurs in 82%-96% of cancer patients receiving chemotherapy (CT) and it is
one of the most prevalent side effects of CT in patients with breast cancer. CT-induced CRF is a distressing,
persistent sense of exhaustion related to the disease or its treatment, and negatively impacts health outcomes
(e.g., depression, sleep disturbance, poor quality of life). Despite various attempts to investigate the etiology of
CRF, the biochemical mechanisms remain elusive. The proposed study aims to investigate the molecular-
genetic pathway of mitochondrial bioenergetics and their association with CT-induced CRF symptoms
experienced by patients with breast cancer receiving CT-containing anthracyclines, compared to those with
non-anthracycline-based CT. Anthracycline-based CT has been associated with mitochondrial dysfunction
through increased mitochondrial reactive oxygen species (ROS) and an induced decrease in muscle strength.
Deficiency of adenosine triphosphate (ATP) has been proposed as the basis of fatigue. Peripheral blood
mononuclear cells (PBMCs) of fatigued patients with prostate cancer has exhibited reduced ATP coupling
efficiency compared to those without fatigue. In patients with prostate cancer undergoing radiotherapy, we
found that CRF severity was significantly correlated with altered mitochondrial genes and impaired
mitochondrial oxidative phosphorylation (OXPHOS). In patients with breast cancer suffering from CT-induced
CRF, we intend to determine whether there is a similar altered expression of mitochondrial-related genes with
defective bioenergetics in PBMCs and platelets. We propose that the chemotherapeutic agent (anthracycline-
based regimen) targets cell cycle progression, which triggers genetic and cellular instability, altering expression
of mitochondrial genes and proteins, inducing reduced electron transport chain (ETC) enzymatic activity and
impaired OXPHOS, resulting in ATP depletion and excessive ROS generation, leading to the development and
intensification of CRF. This R21 proposal will reveal the linkage between changes in the molecular-
genetic pathway of mitochondrial bioenergetics and CT-induced CRF when controlling for relevant
covariates. Specific aims are to: (1) Characterize the profile of mitochondria-related genes associated with
CRF symptoms in patients with breast cancer receiving anthracycline-based CT, compared to patients with
non-anthracycline-based CT at baseline, midpoint, and endpoint of CT. (2) Identify the profile of mitochondrial
bioenergetics associated with CRF symptoms in patients with breast cancer receiving anthracycline-based CT,
compared to patients with non-anthracycline-based CT, at each time point. Understanding the molecular-
genetic bioenergetics underpinning CRF will provide novel insights needed for targeted approaches to mitigate
CT-induced CRF. The results will also advance symptom science, enable us to discover biomarkers, identify
thera...

## Key facts

- **NIH application ID:** 10525505
- **Project number:** 1R21NR020226-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Chao-Pin Hsiao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $241,500
- **Award type:** 1
- **Project period:** 2022-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525505

## Citation

> US National Institutes of Health, RePORTER application 10525505, Unraveling the Associations of Molecular-Genetic Bioenergetics and Chemotherapy-Induced Fatigue Symptoms in Patients with Breast Cancer (1R21NR020226-01A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10525505. Licensed CC0.

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