# PQ2 Obesity-induced fibrocytes promote breast cancer progression

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $349,988

## Abstract

Obesity has been identified as an important risk factor for postmenopausal breast cancer and is significantly
correlated with diminished treatment response. It is currently not understood how inflammation within obese
breast fat contributes to adipose tissue fibrosis and tumor desmoplasia. These conditions have been associated
with both increased breast cancer risk and chemotherapy resistance. The long-term goal is to understand how
obesity increases local and systemic inflammation leading to progression of treatment-resistant breast tumors.
Preliminary studies have shown that transplant of CCL2+ breast stromal cells with transformed breast epithelial
cells promoted rapid breast cancer development, with increased numbers of cancer stem-like cells (CSCs).
Transient depletion of CD11b+ cells early in tumor development resulted in dramatic reductions in cancer
associated fibroblasts (CAFs) and tumor growth rates. Transcriptional analysis of CD11b+ cells from both tumors
and mammary glands of obese mice revealed a fibrotic gene signature and expression of platelet-derived growth
factor receptor alpha (PDGFRα). This fibrotic gene signature is consistent with fibrocytes, which have attributes
of both inflammatory macrophages and myofibroblasts. Based on these preliminary data, the central hypothesis
is that fibrocytes are increased by obesity where they promote aggressive tumor growth and chemotherapy
resistance through the expansion of CSCs via PDGFRα. This hypothesis will be tested with three specific aims:
1) Examine how fibrocytes are recruited to obese mammary fat and promote fibrosis via PDGFRα; 2) Determine
how fibrocytes differentiate into CAFs and promote chemotherapeutic resistance through cancer stem-like cell
(CSC) expansion; 3) Identify how obesity enhances fibrocytes in human breast tissue leading to adipose tissue
fibrosis and desmoplasic, treatment-resistant breast tumors. A high fat diet model of obesity and GFP-labeled
myeloid lineage cells will be used to examine differentiation of obesity-induced fibrocyte populations within the
mammary gland. Gleevec, a clinical PDGFR inhibitor, will be used to target fibrocytes and reduce obesity-
induced fibrosis. Using the inflammatory model of breast tumor progression, the mechanism of fibrocyte-induced
tumor desmoplasia and CSCs expansion will be examined. The efficacy of Gleevec will be tested to reduce
CSCs and enhance chemotherapy response. Reduction mammoplasty tissue from obese and lean women and
well-annotated breast tumor tissue microarrays will be used to understand how obesity alters treatment response
and tumor desmoplasia, and potentially identify patients that might benefit from adjuvant use of Gleevec for
treatment of breast cancer. These studies are innovative because fibrocytes have not been investigated in the
context of obesity. The impact of these studies is that targeted Gleevec therapy to treat desmoplastic tumors in
obese women may significantly improve chemotherapeutic re...

## Key facts

- **NIH application ID:** 9917573
- **Project number:** 5R01CA227542-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** LISA M ARENDT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,988
- **Award type:** 5
- **Project period:** 2018-06-14 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917573

## Citation

> US National Institutes of Health, RePORTER application 9917573, PQ2 Obesity-induced fibrocytes promote breast cancer progression (5R01CA227542-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9917573. Licensed CC0.

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