# Intersection of autophagy and vesicle trafficking in Her2-positive breast cancer

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2024 · $387,251

## Abstract

Breast cancer is the most common malignancy among US women and remains a major health threat with
high incidence and lethality due to therapeutic resistance and metastasis. Breast cancer is also a heterogenous
disease with different subtypes, including HER2+ subtype accounting for about 25% of patients. Despite the
remarkable progress in recent years including anti-HER2 targeted therapy, our understanding of the mechanistic
basis for breast cancer, particularly metastasis is still very limited. The long-term goal of the proposed studies is
to understand the molecular and cellular mechanisms of metastasis and therapeutic resistance of HER2+ and
other breast cancers that are ultimately responsible for patient lethality. In the prior funding period, we generated
and analyzed mouse models for HER2+ breast cancer with deletion of an essential autophagy gene FIP200 or
Fip200-4A mutation specifically blocking its autophagy activity and discovered that blocking FIP200-mediated
autophagy abolished mammary tumorigenesis and metastasis through a new mechanism directly regulating the
oncogenic driver HER2 itself. We showed that autophagy blockade abolishes mammary tumorigenesis and
metastasis by decreasing levels of HER2 on the plasma membrane of mouse and human tumor cells due to
aberrant HER2 trafficking from the Golgi to endosomes and multiple vesicular bodies (MVBs) and eventually
released from tumor cells in small extracellular vesicles (sEVs). Additionally, employing single-cell RNA
sequencing (scRNA-seq) and bioinformatics analysis, we developed a workflow to determine pharmacological
interventions that would yield similar effects as FIP200 ablation. We also found FIP200 acetylation at K276 by
CBP that regulates its stability. Lastly, we performed an in vivo CRISPR-Cas9 screen of a custom designed
library of autophagy regulatory genes using our unique HER2+ mammary tumor cells and identified p47 as a
putative suppressor for HER2+ breast cancer metastasis. Previous studies showed a role for p47 in regulating
membrane fusion events, autophagy, and NFκB signaling, suggesting potential crosstalk between autophagy
with vesicle trafficking in breast cancer metastasis. Based on these strong preliminary data and using our unique
mouse and cell models, we propose to 1) determine the mechanism of autophagy regulation of HER2 trafficking
in mouse and human breast cancer cells, 2) identify pharmacological agents that can disrupt the functions of
FIP200 in mouse and human breast cancer cells as well as patient-derived models, and 3) explore the role and
mechanisms of regulation of HER2+ breast cancer metastasis by p47. Together, these studies will provide
significant insights into the molecular and cellular mechanisms of breast cancer metastasis that may contribute
to novel therapies for this devastating disease.

## Key facts

- **NIH application ID:** 10887642
- **Project number:** 5R01CA211066-07
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** JUN-LIN GUAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,251
- **Award type:** 5
- **Project period:** 2023-07-13 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887642

## Citation

> US National Institutes of Health, RePORTER application 10887642, Intersection of autophagy and vesicle trafficking in Her2-positive breast cancer (5R01CA211066-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10887642. Licensed CC0.

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