Direct Regulation of Estrogen Receptor Transcriptional Activity by NF1
Abstract
The key objective of this project is to define a resistance mechanism for treating ER+ breast cancer by endocrine therapy, such astamoxifen. This project was guided by a clinical study searching for driver mutations that promote resistance to tamoxifen, leading to thediscovery that inactivating NF1 (neurofibromin) is a key factor driving resistance. This project investigates the hypothesis that inactivatingNF1, previously best known as a negative regulator for Ras by acting as a GAP (GTPase Activating Protein), can not only activate Ras, butalso ER by interacting with ERs co-regulators. This is a collaboration between two PIs with complementary expertise. Dr. Chang is amolecular biologist and responsible for Aim 1, which is to investigate NF1s interaction with known ER co-regulator. Dr. Ellis is aphysician scientist who is responsible for Aim 2 to establish a treatment strategy to treat NF1-deficient ER+ breast cancer. We have madegreat stride in this project period from both aims. Briefly, we have uncovered a surprising GAP-independent activity of NF1 that it is also aco-repressor for ER. This is backed by technologically sophisticated RNA-seq and ChIP-seq experiments. As such, inactivating a singletumor suppressor NF1 can activate two powerful oncogenic pathways, which must be co-targeted for effective treatment. To this end, wedemonstrate that using patient-derived xenograft model that this can be achieved by FDA-approved fulvestrant in combination withdabrafenib and trametinib.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2018
- Accession Number
- AD1072402
Entities
People
- Eric Chang
- Matthew J Ellis
Organizations
- Baylor College of Medicine