The Role of NF1 in Mammary Development, Breast Cancer, and Endocrine Resistance
Abstract
When the NF1 gene is mutated in every cell in the body, such as in Neurofibromatosis Type 1, some tissues are more susceptible to cancer than others. Breast tissue is highly susceptible to NF1 mutations, resulting in a significantly higher rate of breast cancer. Not only is breast cancer more common in NF, the rate of death is significantly higher. Few studies are focused on NF-related breast cancer, which is unfortunate, given that standard therapies do not seem to be as effective in individuals with NF compared to the general population. Importantly, both men and women with NF can develop breast cancer. We discovered that the RAS pathway and estrogen-signaling pathway interact to drive breast cancer in NF. These findings were discovered in a first-of-its-kind model of Neurofibromatosis-related breast cancer using an NF1-mutant rat. Our model exhibits aggressive breast cancer and is useful for both drug testing and analysis of mammary tissue during development. We present preliminary data that confirms defective breast development in the NF1-deficient rat leading to altered gland development and a high incidence of breast cancer. Thus, the altered breast development is setting the stage for breast cancer. For other high-risk breast cancer conditions, like BRCA1, prevention strategies are emerging. We propose experiments where we treat our rat models with either estrogen inhibitors or MEK inhibitors to prevent breast cancer from occurring. This type of treatment strategy could be very useful for individuals affected by NF. While the rats are being treated, we will examine the development defects to see whether they are reversed by drugs. We will use cutting-edge analytical techniques that reveal how epigenetic mechanisms and cancer signaling pathways are affected. Also, we will directly examine tumors that have already become resistant to estrogen and MEK inhibitors. Unfortunately, this clinical scenario is common in NF, so it is important to understand how therapy resistance emerges. One of the key resistance mediators is a gene called, AP-1. AP-1 sits downstream of both RAS and the estrogen receptor. We aim to define how NF1 mutations affect AP-1 function in breast precursor cells and cancers. Understanding how AP-1 works will identify new therapy targets and potential biomarkers. These studies will have a tremendous impact on the prevention and treatment of NF-related breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110759
Entities
People
- Matthew R. Steensma
Organizations
- United States Army
- Van Andel Institute