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This research investigates how Gli2 affects the epithelial-to-mesenchymal transition (EMT) in triple negative breast cancer (TNBC).

April 5, 2026

Abstract 4844: Gli2 regulation of EMT in TNBC invasion

Key Points

This research investigates how Gli2 affects the epithelial-to-mesenchymal transition (EMT) in triple negative breast cancer (TNBC).
Pharmacological inhibition of Gli2 was tested in TNBC cell lines.
EMT marker expression was measured post-inhibition.
CUT&RUN sequencing was used to identify Gli2-bound DNA regions.
Genetic knockdown and overexpression experiments were performed on EMT-associated genes in TNBC cell lines.
Transwell migration and invasion assays were conducted on decellularized ECM scaffolds to assess EMT phenotypes.
Reduction of EMT marker expression in TNBC cell lines upon Gli2 inhibition.
Identification of Gli2-targeted genes: Cldn1, Zeb2, and Spp1, with significant fold changes and p-values indicating their roles in EMT regulation.
Proposed studies aim to confirm the direct transcriptional regulation of EMT by Gli2 and its therapeutic implications.

Abstract

Abstract Despite improvements in survival for patients with primary disease only, breast cancer remains a leading cause of cancer-related death for women in part due to the propensity of breast cancer to metastasize and develop therapy resistance. Triple negative breast cancer (TNBC) has high metastatic potential, and an estimated 30-50% of patients develop tumors that are resistant to chemotherapies. To metastasize, tumors undergo epithelial-to-mesenchymal transition (EMT), in which transcriptional alterations allow tumor cells to become more invasive through reduced adhesion and increased motility. In addition to facilitating the early stages of metastasis and allowing tumors to invade, EMT has been associated with a more plastic, stem-like phenotype that may lead to therapy resistance. Thus, preventing the acquisition of an EMT phenotype may offer a dual role in inhibiting metastatic potential as well as resensitizing therapy-resistant tumors in patients with TNBC. While the Hedgehog (HH) signaling pathway is primarily active during embryonic development, its aberrant activation has been observed to promote tumor growth, invasion, metastasis, and chemoresistance. Previous data have shown that components of the HH pathway are upregulated in clinical samples of breast cancer in patients with greater mesenchymal gene signatures and those with metastatic disease. Additionally, Gli2 (Glioma-associated oncogene 2), a downstream transcriptional regulator of HH signaling, correlates with poorer patient outcomes. Thus, we hypothesize that Gli2 transcriptionally regulates EMT-associated genes, therefore promoting invasive potential in TNBC. We examined the pharmacological inhibition of Gli2 and found a reduction in EMT marker expression in TNBC cell lines. Specifically, we have identified genes such as Cldn1 (FC = 0.382, p = 0.0003), Zeb2 (FC = 0.426, p = 0.0005), and Spp1 (FC = 0.163, p = 0.0009) as potential targets of Gli2-mediated EMT. We will use Cleavage Under Targets Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4844.

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