# Defining Breast Tumor Kinase-Dependent Dysregulation of TGF-beta/SMAD Signaling

> **NIH NIH P20** · UNIV OF ARKANSAS FOR MED SCIS · 2024 · $284,335

## Abstract

Summary for Project 2 led by Research Project Leader Sayem Miah, PhD
 The metastatic processes of breast cancer are complex and remain a key area of intense research.
TGFβ/SMAD signaling has been identified as a critical pathway that can be targeted to impact breast cancer
tumorigenesis and metastasis. We made the exciting discovery that breast tumor kinase (BRK)—a non-receptor
tyrosine kinase (nRTK) that is overexpressed in most invasive ductal carcinomas, including the triple-negative
subtype, and linked to proliferation, metastasis, and cancer development—catalyzes tyrosine phosphorylation of
SMAD4, a transcription factor that is a major transducer of TGFβ signaling. Under normal cellular conditions,
SMAD4 interacts with SMAD2/3 to form the SMAD complex and promote the transcription of genes involved in
cellular homeostasis. However, we found that BRK-dependent phosphorylation of SMAD4 inhibits the formation
of the SMAD complex and instead induces an interaction between SMAD4 and the nucleosome remodeling and
deacetylase (NuRD) complex. NuRD is an epigenetic regulator that represses transcription and has been
implicated in triple-negative breast cancer tumorigenesis. Based on our preliminary findings and previously
published reports, we hypothesize that BRK-dependent phosphorylation of SMAD4 facilitates interactions with
the multi-subunit NuRD complex that result in targeted chromatin modification and dysregulation of canonical
TGFβ-stimulated transcription, which promotes tumorigenesis and metastasis. We will test our hypothesis in the
following Specific Aims: (Aim 1) Identify macromolecular protein interactions between BRK-phosphorylated
SMAD4 and the NuRD complex, (Aim 2) Determine how the BRK-phosphorylated SMAD4 with NuRD complex
dysregulates canonical TGFβ-stimulated transcription, and (Aim 3) Determine whether BRK-mediated
dysregulation of canonical TGFβ signaling promotes tumorigenesis and metastasis in vivo. The proposed work
is significant because the oncogene BRK is highly expressed in >85% of human invasive ductal carcinomas,
including the triple-negative subtype. In alignment with the scientific theme of the Center for Molecular
Interactions in Cancer (CMIC), we will elucidate novel molecular features of BRK and SMAD4 that fuel pro-
malignant signaling in breast cancer. COBRE support will help establish my independent research program
through mentoring, career development, and access to Research Cores that are key to the success of the project.

## Key facts

- **NIH application ID:** 10769966
- **Project number:** 1P20GM152281-01
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Md Sayem Miah
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $284,335
- **Award type:** 1
- **Project period:** 2024-03-05 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769966

## Citation

> US National Institutes of Health, RePORTER application 10769966, Defining Breast Tumor Kinase-Dependent Dysregulation of TGF-beta/SMAD Signaling (1P20GM152281-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10769966. Licensed CC0.

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