Role of Core-Binding Factor Rearrangements in Triple-Negative Breast Cancer Progression and Immune Evasion
Abstract
Triple-negative breast cancer (TNBC) is the deadliest breast cancer subtype, accounting for 10%-20% of breast cancer morbidity. Chemotherapy remained the mainstay of intervention for TNBC due to the lack of well-defined genetic targets, and recent genomic sequencing studies have revealed a paucity of TNBC-specific mutations that cause nucleotide changes. Most recently, immunotherapy against the immune checkpoint that prevents immune cells to attack cancer cells emerged as an effective therapy for advanced TNBC tumors overexpressing the immune checkpoint protein programmed death ligand-1, and the patients’ responses appear to be durable. While TNBC tumors are characterized by greater immune cell infiltration, the overall immunotherapy response rates for unselected TNBC are limited to 5%-10%. Thus, discovering the genetic aberrations driving TNBC immune evasion and dysfunction that can be exploited to covert non-responders to responders represents an unmet clinical need. Recurrent gene rearrangements that bring together two gene pieces comprise a class of viable genetic targets that have been matched with several latest breakthrough therapies in solid tumors as exemplified by the first U.S. Food and Drug Administration-approved tumor-agnostic drug against NTRK rearrangements. However, the pathological roles of this class of genetic aberrations in TNBC remain poorly understood due to the complex rearrangements in their genomes. In this project, our landscape study of genomic rearrangements in TNBC revealed recurrent intragenic rearrangements involving Runt-Related Transcription Factor 1 (RUNX1) that result in one or more exons being duplicated or deleted. RUNX1 is a master transcription factor that regulates hematopoiesis in vertebrates and is one of the most frequently mutated genes in leukemia. Emerging evidence also suggest RUNX1 as a key regulator of epithelial cytokine production (cytokines are small signaling proteins that regulate immune response and immune cell recruitment). RUNX1 gene fusions are common in leukemia but are rarely found in solid tumors. Interestingly, RUNX1 rearrangements are preferentially detected in TNBC, which result in in-frame rearranged proteins that disrupt the runt-homology domain. Our preliminary data suggest that RUNX1 rearrangements lead to potent repression of RUNX1 and NFkappaB (NFkB) target genes, resulting in altered tumor-derived cytokine expression in TNBC cells. NFkB is a transcriptional factor that serves as a pivotal mediator of inflammatory responses through regulating the expression of a variety of pro-inflammatory cytokines and is known to be modulated by wild-type RUNX1. RUNX1 rearranged tumors are more aggressive showing larger tumor sizes, geographic necrosis, and relative cold immune microenvironment that lack lymphocyte infiltration (especially cytotoxic and regulatory T cells). In addition, these tumors also exhibit low interferon gamma signature that detects gene expression from activated immune cells and measures the overall anti-tumor immune response. Such tumors are deemed to be kiss of death that will otherwise have a devastating clinical outcome. We are very excited about our finding, which represents a potential transformative concept in breast cancer genetics interfacing with immune response that has significant game-changing potential. This project will examine the immune microenvironment of RUNX1-rearranged TNBC tumors using clinical samples; elucidate the function of RUNX1 rearrangements on immune cell trafficking, tumor progression, and immunotherapy resistance in vitro and in vivo; determine how RUNX1 rearrangements orchestrate cytokine and chemokine contexture in breast cancer cells; and explore new immunotherapy strategies such as in situ cytokine therapy. Successful outcome of this project will shed new light on a dark area of breast cancer genetics underlying immune evasion and will pave the way to novel immunotherapeutic strategies to tackle these
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211037
Entities
People
- Binfeng Lu
Organizations
- United States Army
- University of Pittsburgh