Therapeutic Targeting of Nuclear Hormone Receptors in Neurofibromin/NF1-Depleted Breast Cancer
Abstract
This project centers on the NF1/neurofibromin tumor suppressor, which was best known as a GTPase Activating Protein (GAP) that represses Ras activity. We have recently shown that NF1 has a GAP-independent activity by functioning also as a transcriptional corepressor for estrogen receptor alpha (ER) in ER+ breast cancer. ER is structurally closely related to the androgen receptor (AR). In this multi-PI grant, we will investigate the hypothesis that We hypothesized that NF1, analogous to its role in ER regulation, is also an AR corepressor. Our objective is to assess this hypothesis to explore and exploit the broader consequences of NF1 loss in breast cancer therapeutics. The first specific aim is to define the interactions between neurofibromin and AR by studying neurofibromins role as an AR co-repressor. Our results showed that AR and NF1 can physically interact in a ligand-dependent manner. While NF1-silencing enhanced AR-dependent transcriptional activities, NF1 overexpression inhibited it. As a result, NF1-depleted AR+ cancer cells can grow at suboptimal levels of AR agonists. The second specific aim is to assess how hyperactivated AR due to NF1 loss impacts the treatment of breast cancer by pre-clinically modeling the effects of AR antagonists or SARMs (selective AR modulators). The results from this project period showed that NF1-depletion can affect the choices of anti-AR agents. Enzalutimde which does not have known agonist activity is a better drug to treat these tumors than bicalutamide. Further NF1 loss actives not only AR but also Ras. In support of this, adding a MEK inhibitor can enhance the efficacy of enzalutamide.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2024
- Accession Number
- AD1230223
Entities
People
- Alastair Thompson
- Eric Chang
Organizations
- Baylor College of Medicine