# Targeting MUC5AC mucin in breast cancer brain metastasis

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $451,543

## Abstract

Abstract
Breast cancer (BC) brain/central nervous system (CNS) metastasis is associated with poor survival among U.S.
women, with 30-40% of these cases reported as triple receptor-negative (TN) and epidermal growth factor
receptor-positive (ErbB2+) BC subtypes. Despite the progress in the diagnostic and therapeutic management of
BC, there is still a significant increase in brain metastasis (BM) cases, and the survival rate among these BCBM
patients is very bleak. Therefore, there is an urgent need to identify primary molecular drivers of BCBM and
novel predictive biomarker(s) for the early detection of BM. In this regard, our global transcriptomic analysis
showed that levels of a secretory gel-forming mucin, MUC5AC, is significantly higher in the brain tropic (BT) cells
than the parental BC cells. Additionally, an in silico analysis revealed significantly higher levels of MUC5AC in
the archived BCBM tissues compared to the primary tumors. Most importantly, the augmented levels of MUC5AC
were detected in the serum of BCBM patients compared to non-BM BC patients. These studies strongly suggest
that MUC5AC could be a potential predictive biomarker for the early detection of BCBM. Furthermore, MUC5AC
knockdown (KD) resulted in reduced motility, cell adhesion, and blood-brain barrier (BBB) transmigration in BT
cell lines relative to controls. Importantly, MUC5AC KD cells showed diminished BM potential in an intracardiac
mouse model. Our initial mechanistic studies on the MUC5AC-mediated BM showed an important role of the
CD44 and cMET pathways in BT cells. MUC5AC interacted with CD44v6, a co-receptor for cMET, and co-
localized with the activated form of cMET to establish BCBM. CD44v6 and cMET have been shown to
preferentially enhance BM through a feed-forward loop using hyaluronic acid and hepatocyte growth factor
pathways. We also observed robust expression of MUC5AC in BT cells in the presence of microglia/astrocyte
conditioned media. Targeting MUC5AC with PLB-1001 reduces MUC5AC expression in BT cells. We
hypothesize that “MUC5AC enhances BCBM through CD44v6/cMET-axis” and could thus be a useful marker to
predict BCBM. In Aim 1, we will establish MUC5AC as a novel predictive biomarker for BM in high-risk BC
patients, and examine whether high MUC5AC expression in primary tumors predicts BM, and correlates with
response to therapy, overall survival, and relapse. Aim 2 studies will define the regulation of MUC5AC-mediated
BM through the cMET/CD44v6/NF-κB-axis using preclinical mouse models. In Aim 3, we will use a BBB
penetrable phase 1 tested cMET inhibitor alone or in combination with cisplatin or neratinib as novel therapeutic
strategy for TN and ErbB2+ brain metastatic BC. Altogether, the proposed studies will establish MUC5AC as a
novel predictive biomarker for high-risk BM and will help in developing preventive strategies for BCBM, which
currently has no cure.

## Key facts

- **NIH application ID:** 10334526
- **Project number:** 5R01CA241752-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Mohd Wasim Nasser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $451,543
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334526

## Citation

> US National Institutes of Health, RePORTER application 10334526, Targeting MUC5AC mucin in breast cancer brain metastasis (5R01CA241752-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10334526. Licensed CC0.

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