Alternative NF1 Isoforms in RAS Deregulation and Breast Cancer Progression
Abstract
When the NF1 gene is mutated in every cell in the body, such as in Neurofibromatosis Type 1, there are tissues that are negatively affected more 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 RNA produced by the mutant NF1 gene competes with the RNA produced by the normal NF1 gene, resulting in a variety of negative consequences in cells isolated from breast tissue. Furthermore, we discovered that breast cancer cells with NF1 mutations behave more aggressively when the mRNA processing is altered. Thus, it is not always the gene mutation that blocks production of the neurofibromin protein, resulting in activation of the RAS; the mRNA produced by the NF1 gene can be processed incorrectly resulting in a variety of cellular abnormalities. We developed a first-of-its-kind model of Neurofibromatosis-related breast cancer in the rat. This model exhibits aggressive breast cancer and is useful for both drug testing and mRNA analysis. We present preliminary data that confirms alteration of mRNA is a bona fide driver of breast cancer in NF. Our next step is to determine exactly how the mRNA is altered. Is it defective processing? Or does the natural mRNA variation become altered in the presence of various mutations? We employ a novel sequencing technique that requires an entire mRNA fragment as input. Normally, small fragments of mRNA need to be sequenced and then reassembled resulting in significant accumulation of errors. Whole mRNA inputs will provide us with a never-before-seen look at mRNA processing in NF1 deficient cells. We will then extend our observations into human breast cancer using established databases. Our therapeutic strategy is to target both RAS and estrogen signaling using RAS (i.e., MEK) inhibitors and a new drug obtained from the Genentech Company called a SERD. Next-generation SERDs are oral agents with significantly fewer side effects than the original drugs that have been used for decades (e.g., fulvestrant). Our preliminary data confirm an exquisite response to these drugs in our NF1-deficient rats. We developed therapy-resistant lines that will be investigated to determine whether mRNA processing ultimately causes drug resistance. The results of these studies will greatly impact our fight against NF-related breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110224
Entities
People
- Matthew R. Steensma
Organizations
- United States Army
- Van Andel Institute