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, suchas tamoxifen. This project was guided by a clinical study searching for driver mutations that promote resistance to tamoxifen,leading to the discovery that inactivating NF1 (neurofibromin) is a key factor driving resistance. This project investigates thehypothesis that inactivating NF1, previously best known as a negative regulator for Ras by acting as a GAP (GTPaseActivating Protein), can not only activate Ras, but also ER by interacting with ERs co-regulators. This is a collaborationbetween two PIs with complementary expertise. Dr. Chang is a molecular biologist and responsible for Aim 1, which is toinvestigate NF1s interaction with known ER co-regulator. Dr. Ellis is a physician scientist who is responsible for Aim 2 toestablish a treatment strategy to treat NF1-deficient ER+ breast cancer. We have made great stride in this project period fromboth aims. Briefly, we have uncovered a surprising GAP-independent activity of NF1 that it is also a co-repressor for ER. Thisis backed by technologically sophisticated RNA-seq and ChIP-seq experiments. As such, inactivating a single tumorsuppressor NF1 can activate two powerful oncogenic pathways, which must be co-targeted for effective treatment. To this end,we demonstrate that using patient-derived xenograft model that this can be achieved by FDA-approved fulvestrant incombination with dabrafenib and trametinib.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2019
- Accession Number
- AD1097574
Entities
People
- Eric Chang
- Matthew J Ellis
Organizations
- Baylor College of Medicine