# Role of tumoral derived CCL2 in skeletal muscle wasting in breast cancer

> **NIH NIH R03** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $76,500

## Abstract

Abstract
A complicating factor in the treatment of advanced breast cancer is skeletal muscle wasting. Approximately 15-
40% of breast cancer patients show signs of skeletal muscle wasting, which contributes to weakness, fatigue
and limits the ability of patients to tolerate anti-cancer medication, adversely affecting patient survival. For
breast cancer patients, diagnosis and treatment of skeletal muscle wasting may be complicated by unique
factors. Skeletal muscle wasting may be masked by high BMI caused by accumulation of adipose tissue in
place of muscle tissue. Treatment is complicated by the presence of differing molecular subtypes including
luminal, Her2 and basal-like breast cancers, which express varying levels of inflammatory cytokines and
growth factors that may not only contribute to cancer progression, but also cause changes to muscle
physiology. By understanding the molecular and cellular processes of skeletal muscle wasting in breast
cancer, we may identify more effective targeted treatments to alleviate muscle wasting and enhance
effectiveness anti-cancer therapies. CCL2 is a well-known regulator of macrophage recruitment during
inflammation and breast cancer progression, and mediates muscle repair. We had previous shown that CCL2
is most highly expressed in basal-.like breast cancers, a particularly aggressive breast cancer subtype. In the
MDA-MB231 model of basal-like breast cancer, tumoral CCL2 expression was localized to muscle tissues,
corresponding to increased inflammation, and expression of LC3B, an autophagy marker, MuRF1 and Atrogin
1, protein degradation markers, which are hallmarks of muscle wasting. These phenotypes were reduced with
CCL2 knockdown in the primary tumor. Treatment of myoblasts with increasing doses of CCL2 or tumor
conditioned medium inhibited cell proliferation and myotube formation. Treatment of myotube cultures
increased MuRF1, Atrogin-1 and LC3B expression. Cytokine array analysis of breast cancer cells and
datamining analysis revealed significant associations between CCL2 and IL12 and IL6, inflammatory cytokines
that may be important in skeletal muscle wasting. We hypothesize that increased CCL2 expression in breast
tumors cooperates with IL6 or IL12 to promote skeletal muscle wasting. 2 aims are proposed. Aim 1 is to
determine the contribution of tumoral CCL2 to breast cancer associated skeletal muscle wasting relative to IL6
and IL12 using the 4T1 model of basal-like breast cancer. Aim 2 is to determine the functional contribution of
CCL2 to myotube atrophy and impairment of muscle regeneration, relative to IL6 and IL12 using 3D cell culture
models. This multi-interdisciplinary project involves experts on breast cancer and muscle physiology. These
pilot studies would provide justification for long-term studies investigating the role and mechanisms of these
cytokines in breast cancer associated muscle wasting, with the long-term goal of developing targeted therapies
to alleviate muscle wasting and...

## Key facts

- **NIH application ID:** 9854904
- **Project number:** 5R03CA227359-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Nikki Cheng
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $76,500
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854904

## Citation

> US National Institutes of Health, RePORTER application 9854904, Role of tumoral derived CCL2 in skeletal muscle wasting in breast cancer (5R03CA227359-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854904. Licensed CC0.

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