# TGFBI in the breast cancer microenvironment promotes TGF-B signaling to increase tumor progression

> **NIH NIH F31** · DUKE UNIVERSITY · 2020 · $31,021

## Abstract

SCOPE OF WORK
Despite advances in therapy, breast cancer remains the second leading cause of cancer related deaths in
women. As breast cancer cells are genetically unstable and heterogeneous, focusing on the tumor
microenvironment (TME) has the potential to identify new therapeutic targets. One important cytokine in the TME
for many cancers is the TGF-β1 ligand that binds TGF-β receptors to promote Smad signaling and gene
expression. The TGF-β signaling pathway has well established roles in regulating cellular homeostasis, including
proliferation, differentiation and apoptosis. During cancer initiation and progression, the TGF-β signaling pathway
is disrupted in a cell and context specific manner. In breast cancer, TGF-β suppresses tumor initiation, but in
established cancers, promotes cancer progression to increase invasion and metastasis. As such, TGF-β is an
attractive cancer therapeutic target. However, targeting the TGF-β signaling pathway directly has not been
successful in the clinic partially due to an incomplete understanding of how TGF-β’s role changes during cancer
progression. To gain insight into factors that may regulate TGF-β signaling in the tumor microenvironment, we
performed a proteomic screen of the breast cancer secretome and identified the integrin binding protein βIGH3
as a protein able to promote TGF-β signaling. CRISPR/Cas9 silencing of βIGH3 decreases tumor growth and
metastasis in a breast cancer model. This decrease in tumor progression was also associated with decreased
TGF-β signaling in vivo.
We hypothesize that βIGH3 increases breast cancer progression by promoting TGF-β-induced EMT, migration
and invasion, with effects on TGF-β signaling mediated by increasing active TGF-β1 ligand through proteases.
To address this hypothesis, we propose two aims. Aim 1: To establish whether βIGH3 induces TGF-β signaling
by increasing the activation of mature TGF-β1 ligand from the latent-TGFβ precursor. Aim 2: To determine
whether βIGH3 increases metastasis by promoting TGF-β signaling and TGF-β induced EMT associated
migration, invasion and extravasation. Defining the detailed mechanism of how βIGH3 increases tumorigenesis
through TGF-β signaling could potentially lead to a new therapeutic target in breast cancer.

## Key facts

- **NIH application ID:** 10005812
- **Project number:** 5F31CA236484-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Armando L Corona
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,021
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005812

## Citation

> US National Institutes of Health, RePORTER application 10005812, TGFBI in the breast cancer microenvironment promotes TGF-B signaling to increase tumor progression (5F31CA236484-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10005812. Licensed CC0.

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