# KLF4-mediated myeloid plasticity in breast cancer recurrence

> **NIH NIH SC3** · BENEDICT COLLEGE · 2022 · $97,389

## Abstract

Breast cancer patients have an anomalously high rate of relapse or recurrence from dormancy after
surgery or immunotherapy. There is a major lack of understanding of what regulates dormancy, and basic
and translational research is badly needed in this area. Thus, characterization of novel cell types and the
underlying signaling molecules in tumor recurrence will likely reveal optimal therapeutic targets to
prevent/treat breast cancer recurrence from dormancy. At a cellular level, we propose that a specific type
of bone marrow-originated cells known as fibrocytes inhibit breast cancer dormancy. This proposal is
supported by published data showing that: 1). fibrocytes promote metastatic tumor growth in a mouse
model of melanoma. 2). fibrocytes contribute to tumor progression via immune evasion. 3). fibrocytes
possess the ability to generate fibroblasts, a major type of stromal cells supporting growth of high grade
breast cancer. At a molecular level, we propose that a nuclear protein named Kruppel like factor 4 (KLF4)
is critical to the generation of fibrocytes in regulating breast cancer dormancy because: 1). KLF4 deficiency
drastically decreased the tumor growth in the metastatic lung in mouse models of breast cancer
metastasis. This was accompanied by decreased numbers of fibrocytes. 2). KLF4 expression levels were
tightly associated with the efficiencies of fibrocyte generation and expression levels of a protein named
fibroblast-specific protein 1 (FSP1). Highly expressed FSP1 has been linked to recurrent mammary tumors.
We thus hypothesize that fibrocytes promote breast cancer recurrence from dormancy in a
KLF4/FSP1 axis-dependent manner. We designed the following three specific aims to test our
hypothesis. In Aim 1, we will isolate KLF4-deficient fibrocyte precursor cells from KLF4-deficient mice. In
Aim 2, we will perform a cause-effect study testing whether KLF4 deficiency in fibrocyte precursor cells
leads to reduced tumor recurrence in two mouse models of breast cancer. In Aim 3, we will establish a
mechanistic link between the KLF4/FSP1 signaling and breast cancer recurrence. We anticipate that our
studies will reveal a novel function of KLF4-controlled fibrocytes in breast cancer recurrence from
dormancy. Successful completion of the project will be very helpful to determine whether KLF4 or its
downstream molecules is a novel therapeutic target to extend tumor dormancy or eradicate dormant tumor
cells in breast cancer patients.

## Key facts

- **NIH application ID:** 10401468
- **Project number:** 5SC3GM136639-03
- **Recipient organization:** BENEDICT COLLEGE
- **Principal Investigator:** Walden Ai
- **Activity code:** SC3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $97,389
- **Award type:** 5
- **Project period:** 2020-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401468

## Citation

> US National Institutes of Health, RePORTER application 10401468, KLF4-mediated myeloid plasticity in breast cancer recurrence (5SC3GM136639-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10401468. Licensed CC0.

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