# Conserved coamplification event in HER2+ breast cancer increases metastasis

> **NIH NIH F31** · MICHIGAN STATE UNIVERSITY · 2024 · $25,662

## Abstract

PROJECT SUMMARY
 Breast cancer is the most common cancer diagnosed among women and is estimated to be the leading
cause of death for women worldwide. Approximately one fifth of breast cancer patients’ tumors overexpress the
human epidermal growth factor receptor 2 (HER2) protein; this is the result of an amplification event on the long
arm of human chromosome 17, leading to high copy number gains of the HER2/Neu gene (ERBB2). Metastatic
HER2+ breast cancer is more aggressive than other subtypes of breast cancer, responds poorly to general
chemotherapy, and is invariably fatal. Lack of understanding of the molecular mechanisms that underpin the
metastatic cascade leads to limited therapy options and poor clinical outcomes. To study the mechanisms of
metastasis in HER2+ breast cancer, we utilize a transgenic mouse model which overexpresses Neu, the rat
isoform of HER2, under control of the mouse mammary tumor virus (MMTV) promoter, henceforth known as
MMTV-Neu. Interestingly, our recent paper describing whole genome sequencing (WGS) of MMTV-Neu primary
tumors revealed a coamplification event centered on mouse chromosome 11qD, near Erbb2, in a majority of
samples. Comparing these results to human genomic data through The Cancer Genome Atlas (TCGA) reveals
an analogous amplification event on the highly syntenic human chromosome 17q21.33 near, but separate from,
the ERBB2 amplicon. This secondary amplicon was found to be present in 25% of HER2+ patients, 9% of all
breast cancers, and contains a number of candidate genes that putatively mediate metastasis. Preliminary data
addresses the potential for these candidate genes in mediating metastasis, but the molecular mechanisms for
how this occurs remains unknown. The central hypothesis of this proposal is that upregulation of three genes
in this amplicon, collagen type 1 alpha 1 chain (Col1A1), chondroadherin (CHAD), and prohibitin (PHB),
increases metastasis through alterations to the tumor microenvironment and oncogenic signaling pathways. This
hypothesis will be evaluated using three independent aims that will collectively identify key events and
dependencies in the HER2+ metastatic cascade. Aim 1 identifies the stage of metastasis affected by the
17q21.33 amplicon by knockout/knockdown and overexpression of the three candidate genes in HER2+/Neu
overexpressing cell lines injected into syngeneic mice. Aim 2 utilizes transcriptomic differences between tumors,
immunohistochemistry (IHC), and co-immunoprecipitation (Co-IP) to determine signaling network differences
between tumors +/- for candidate genes and spatial expression of genes within the tumor. Aim 3 determines
what genes in the amplicon are necessary or sufficient to increase metastasis by overexpressing candidate
genes alone or in tandem and measuring effects on migration and metastasis. The long-term objectives and
broad goals of this hypothesis driven proposal are to provide an increased understanding of why some breast
cancers become metasta...

## Key facts

- **NIH application ID:** 10948068
- **Project number:** 5F31CA271689-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Carson Dennis Broeker
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $25,662
- **Award type:** 5
- **Project period:** 2023-09-29 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948068

## Citation

> US National Institutes of Health, RePORTER application 10948068, Conserved coamplification event in HER2+ breast cancer increases metastasis (5F31CA271689-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10948068. Licensed CC0.

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