The Role of NF1 in Mammary Development, Breast Cancer, and Endocrine Resistance
Abstract
Neurofibromatosis type I (NF) patients have a significantly increased risk of dying from breast cancer. Our studies have revealed previously unknown interactions between NF1, RAS deregulation, and estrogen receptor (ER) signaling. NF1 is the key negative regulatory gene of the RAS pathway and NF1 mutation or deletion results in aberrant RAS pathway activation. AP-1 is a heterodimeric transcription factor activated by RAS-ERK signaling that plays a pivotal role in differentiation and cell identity through enhancer binding and chromatin remodeling. In breast cancers, AP-1 can promote endocrine resistance by altering the ER cistrome and transcriptome. Together, these results strongly suggest that NF1 loss of function promotes tumor initiation and endocrine resistance through deregulated AP and ER signaling and altered mammary progenitor differentiation. We hypothesize that NF1 deficiency promotes breast cancer and endocrine resistance in NF1-related and sporadic breast cancer by altered AP-1 and ER signaling and chromatin remodeling. This proposal will integrate novel NF1 models and innovative technologies to resolve the role of NF1 function in mammary development, breast cancer initiation, and endocrine-resistance. Moreover, this study may reveal RNA or chromatin signatures that could serve as diagnostic or prognostic markers forNF1-related breast cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2022
- Accession Number
- AD1191215
Entities
People
- Matthew R. Steensma