Direct Regulation of Estrogen Receptor Transcriptional Activity by NF1
Abstract
The key objective of this project was to define a resistance mechanism for treating ER+ breast cancer by endocrine therapy, such as tamoxifen. This project investigated the hypothesis that inactivating the tumor suppressor NF1 (neurofibromin), previously best known as a negative regulator for Ras by acting as a GAP (GTPase Activating Protein), can not only activate Ras, but also ER, by interacting with ERs co-regulators. This is a collaboration between two PIs with complementary expertise. Aim 1 is the main responsibility of Dr. Chang, a molecular biologist, to investigate NF1s interaction with known ER co-regulator. Dr. Ellis is a physician scientist who is responsible for Aim 2 to establish a treatment strategy to treat NF1- deficient ER+ breast cancer. We have made great stride in this study from both aims and the results have been published in a high impact journal Cancer Cell. Briefly, we discovered a surprising GAP-independent activity of NF1 that it is also a corepressor for ER. As such, inactivating a single tumor suppressor 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 in combination with binimetinib, a new generation MEK inhibitor. This treatment strategy is the basis of a NCI ComboMATCH-supported phase-II trial, thus fulfilling the promise of translating laboratory study into clinical practice.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2021
- Accession Number
- AD1152686
Entities
People
- Eric Chang
- Matthew J Ellis
Organizations
- Baylor College of Medicine