# FLI1 Expression in Invasive Breast Carcinoma: Clinicopathological Correlations and Prognostic Implications

## TL;DR

This study explores how FLI1 expression in breast cancer relates to tumor aggression and response to LSD1 inhibitors, suggesting FLI1 could be a marker for treatment response.

## Contribution

The study reveals FLI1's dual role in tumor progression and its regulation by LSD1, offering new insights into breast cancer aggressiveness and epigenetic therapy response.

## Key findings

- High FLI1 expression correlates with advanced histological grade in invasive breast carcinoma.
- FLI1-high tumors show elevated stromal and immune scores, indicating tumor microenvironment remodeling.
- LSD1 inhibition downregulates FLI1 target genes involved in angiogenesis and invasion.

## Abstract

Background: The E26 transformation-specific (ETS) transcription factor Friend Leukemia Integration 1 (FLI1) has been linked to breast cancer aggressiveness, stromal remodeling, and immune modulation, yet the regulatory mechanisms governing its activity remain poorly defined. Of note, various studies have shown that EWS-FLI1-mediated transcription programs are facilitated via direct recruitment and binding of the NuRD-LSD1 complex, regulating its associated gene targets. Furthermore, LSD1 inhibition exhibited reverse transcriptional profiles driven by ETS-FLI and reduced in vivo tumorigenesis in cancers. Methods: We evaluated FLI1 expression across multiple invasive breast carcinoma (IBC) cohorts to determine its prognostic significance and associations with stromal features. In parallel, we investigated FLI1 regulation in humanized breast cancer mouse models treated with an LSD1 inhibitor. Results: High FLI1 expression was associated with advanced histological grade in IBC, consistent with an oncogenic function. FLI1-high tumors also exhibited elevated stromal and immune scores, indicating a role in remodeling the tumor microenvironment. Additionally, LSD1 inhibition downregulated FLI1 target genes involving angiogenesis and invasion. Conclusions: These findings highlight the dual role of FLI1: tumor-intrinsic FLI1 promotes proliferation and invasion, whereas its transcriptional regulation in tumor and endothelial compartments likely reflects LSD1 dependence. Collectively, our results support a mechanistic model in which LSD1–FLI1 crosstalk is involved in immune and stromal remodeling, positioning FLI1 as both a marker of tumor aggressiveness and a potential predictor of response to epigenetic therapies in breast cancer.