# Pleiotropic functions of FOXC2 in EMT, stem cells and breast cancer progression

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $1,007

## Abstract

Development of resistance to therapies, tumor relapse, and metastasis pose significant risks to breast cancer
patients and are responsible for the majority deaths among these cancer patients. Recent studies have
demonstrated that the developmental process is known as epithelial-mesenchymal-transition (EMT) as well as
a subpopulation of cancer cells termed cancer stem cells (CSC), in these various processes. We and others
have shown that the EMT program and stem cell properties are interconnected, and specifically, cancer cells
are capable of acquiring stem cell attributes through the activation of EMT. This suggested that targeting EMT
program may reduce the disease burden and will decrease death among cancer patients. However, the dearth
of signaling pathways emanating from the tumor microenvironment capable of inducing EMT - including
inflammatory cytokines and transforming growth factor β-1 (TGFβ1) makes it impossible to therapeutically target
EMT. Cumulative studies from our laboratory over the last 9 years have resulted in the seminal identification of
the transcription factor FOXC2, as a key player in metastasis and also as a common downstream effector of
multiple EMT-signaling pathways and indispensable for the procurement of CSC properties. A characteristic
feature of CSCs is their capability to self-renew via asymmetrical or symmetrical self-renewal type of cell divisions
thereby enabling the continued existence and expansion of the CSC pool. The current proposal will
systematically test the role of FOXC2 as a critical element of the molecular switch facilitating CSC self-renewal
and expansion, and investigate if aberrant activation of FOXC2 leads to increase in CSC populations via Notch
signaling, resulting in tumor progression and metastasis. We will use a combination of in vitro-, and in vivo tumor
models, and patient-derived xenografts as well as genetically engineered mouse models to tease out this
process. We will also examine the function of TGFβ1, a physiologically relevant inducer of EMT, in dictating
FOXC2-induced CSC expansion. Also, we will evaluate FOXC2-regulated mitotic bookmarking in maintaining
the identity of the CSCs following stem cell division. Finally, we will test select small molecule inhibitors capable
of modulating FOXC2-function in selectively preventing CSC expansion during EMT. Significance: In summary,
our proposal will not only help clarify the fundamental processes regulating CSC self-renewal and expansion of
CSCs during EMT but will also contribute to designing novel strategies that would provide an opportunity to shift
the balance of CSC towards more differentiated cells and exhaust therapy-resistant, metastasis-prone CSCs.

## Key facts

- **NIH application ID:** 10477993
- **Project number:** 5R01CA155243-10
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Sendurai Ayyavoo Mani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,007
- **Award type:** 5
- **Project period:** 2011-03-16 → 2022-12-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477993

## Citation

> US National Institutes of Health, RePORTER application 10477993, Pleiotropic functions of FOXC2 in EMT, stem cells and breast cancer progression (5R01CA155243-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10477993. Licensed CC0.

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