Amplification Events Altering Tumor Microenvironment That Drive Metastasis in HER2+ Breast Cancer
Abstract
Overarching Challenge: This application will address the challenges of: “Identify why some breast cancers become metastatic.” Rationale: HER2 is a gene associated with breast cancer. In 20%-30% of breast cancer, there are too many copies (amplification) of the HER2 gene, resulting in the HER2 pathway being turned on with no means to turn it off. In 25% of the HER2+ve patients, we identified an additional amplification event that we link to metastasis and have hypothesized that genes in this event regulate metastasis. This spread of the tumor to distant sites is what causes patient mortality. In preliminary work, we have knocked out genes in this genetic event, resulting in reduction in metastasis. We propose to characterize the mechanisms leading to metastasis in this model system. Objective: We have proposed to investigate the mechanism of HER2 metastasis through a combination of bioinformatics, knockout, and drug studies. Precisely, we will focus on the role of a number of genes that are co-amplified with 25% of HER2+ve patients in a separate amplification event and the role these genes have in regulating metastasis. Aims: To achieve this objective, we will examine the following three aims: Specific Aims: 1. Establish the stage of metastasis altered by altered gene expression from the 11D amplicon. Through a combination of genetic studies, we will determine what stage of metastasis (exit from primary tumor, entry to blood vessels, survival in blood vessels, exit from blood vessels at distant site or colonization of distant site) the amplification event is regulating. 2. Elucidate the signaling mechanism that the amplicon functions through to regulate metastasis. Given the link between the amplicon and activation of key cell signaling pathways, we will determine which signaling mechanisms are affected by the secondary amplification event in HER2+ve breast cancer. 3. Screen transcriptional profiles of primary tumors and metastases with 11D amplification for vulnerabilities. Given the importance of metastasis to survival, we will examine genes that are expressed in primary tumors with and without 11D amplification as well as metastases. These genes will be screened for potential therapeutic targets. The identification of therapies will be followed by preclinical validation. Patient Population: This study targets 25% of patients with HER2+ve breast cancer as well as a subset of other breast cancer patients (5% luminal A and 6% luminal B) with amplification of the Col1A1/CHAD/PHB locus. Potential Clinical Applications, Benefits and Risks: Uncovering the mechanism by which HER2 metastasis occurs has several potential clinical applications. This is a basic research project and the potential clinical applications are preliminary. With the successful completion of this proposal, we will have made the first effort towards identifying genes that will function as biomarkers for metastatic progression. This would allow for establishment of potential risk, closer follow-up, and potential preventative interventions to occur. Our preclinical drug screen may also reveal a susceptibility and new treatment opportunities for metastatic breast cancer. Projected Time to Patient-Related Outcome: The projected time to patient outcome is difficult to estimate given that this is a basic research proposal. Indeed, given that the mechanism is currently unknown, this proposal may open a new area of investigation prior to direct impact. Impact on Ending Breast Cancer: As stated above, this is a basic proposal. However, understanding the mechanism of HER2 metastasis may lead to mechanisms preventing mortality. Ultimately this is high-risk/high-reward proposal due to this potential.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110002
Entities
People
- Eran R Andrechek
Organizations
- Michigan State University
- United States Army