# Mechanisms of systemic dysfunction responsible for exercise intolerance induced by breast cancer, cytotoxic chemotherapy, and endocrine therapy in Veterans

> **NIH VA IK2** · VA SALT LAKE CITY HEALTHCARE SYSTEM · 2021 · —

## Abstract

Breast cancer is the most prevalent cancer affecting women in the U.S. (1/8 lifetime probability of diagnosis).
With the growing number of women Veterans (>2 million) exhibiting a 20-40% greater probability of diagnosis,
this a serious concern recognized by the VA. The majority of breast cancers are diagnosed in stage I-III and are
treated by cytotoxic or endocrine therapies. Detrimentally, these patients have exercise intolerance that hinders
physical function and quality of life. Far-reaching systemic dysfunction is likely induced by the pernicious effects
of breast cancer, which are exacerbated by cytotoxic and endocrine therapies. Such, peripheral, sequelae are
promising therapeutic targets to mitigate the secondary effects of breast cancer and these therapies causing
exercise intolerance, thus improving these essential anticancer therapies and preserving quality of life. Thus,
there is a pressing, and unmet, need to identify the sites and underlying mechanisms of systemic dysfunction
and exercise intolerance induced by stage I-III breast cancer and cytotoxic and endocrine therapies. Reactive
oxygen/nitrogen species (ROS) are elevated in patients with breast cancer prior to surgery/treatment and
undergoing cytotoxic or endocrine therapies, which is a likely mechanism mediating systemic dysfunction.
Critically, the peripheral vascular, mitochondrial, and neuromuscular systems are primary sites contributing to
exercise intolerance in health and disease that are vulnerable to elevations in ROS, making these likely sites of
systemic dysfunction leading to exercise intolerance induced by breast cancer and cytotoxic and endocrine
therapies. The recent development of the mitochondrial-targeted antioxidant mitoquinone (Mito-Q) provides an
innovative opportunity to reveal the mechanistic, causal role of ROS. The focus of this application is to determine
sites (peripheral vascular, mitochondrial, and neuromuscular systems) and underlying mechanisms (elevated
ROS) contributing to the exercise intolerance induced by stage I-III breast cancer (Phase A) and cytotoxic and
endocrine therapies (Phase B). Our central hypothesis is that systemic vascular, mitochondrial, and
neuromuscular dysfunction and exercise intolerance are induced by stage I-III breast cancer and exacerbated
by cytotoxic and endocrine therapies, and these can be mitigated by preventing the increase in systemic ROS.
Accordingly, the systemic effects of stage I-III breast cancer (Phase A) and cytotoxic and endocrine therapies
(Phase B) will be determined by the passive leg movement (PLM) assessment of vascular function (Specific
Aim 1), permeabilized muscle fiber mitochondrial respiration assessment of skeletal muscle mitochondrial
function (Specific Aim 2), and knee-extensor exercise tolerance combined with electrical nerve stimulation
peripheral/central fatigue assessment of neuromuscular function (Specific Aim 3). Importantly, the proposed
research will address a Women Veteran’s health pr...

## Key facts

- **NIH application ID:** 10250711
- **Project number:** 1IK2CX002114-01A2
- **Recipient organization:** VA SALT LAKE CITY HEALTHCARE SYSTEM
- **Principal Investigator:** Ryan Michael Broxterman
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250711

## Citation

> US National Institutes of Health, RePORTER application 10250711, Mechanisms of systemic dysfunction responsible for exercise intolerance induced by breast cancer, cytotoxic chemotherapy, and endocrine therapy in Veterans (1IK2CX002114-01A2). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10250711. Licensed CC0.

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