The ELK3-GATA3 axis orchestrates invasion and metastasis of breast cancer cells in vitro and in vivo

Abstract

Triple-negative breast cancer is a highly aggressive tumor subtype that lacks effective therapeutic targets. Here, we show that ELK3 is overexpressed in a subset of breast cancers, in particular basal-like and normal-like/claudin-low cell lines. Suppression of ELK3 in MDA-MB-231 cells led to transdifferentiation from an invasive mesenchymal phenotype to a non-invasive epithelial phenotype both in vitro and in vivo. Suppression of ELK3 resulted in extensive changes in genome expression profiles. Among these, GATA3, a master suppressor of metastasis, was epigenetically activated. Also, suppression of GATA3 led to the restoration of migration and invasion. These results suggest that the ELK3-GATA3 axis is a major pathway that promotes metastasis of MDA-MB-231 cells.

Silencing of ELK3 Induces S-M Phase Arrest and Apoptosis and Upregulates SERPINE1 Expression Reducing Migration in Prostate Cancer Cells

“…ELK3 (also called Net, SAP-2, or ERP) is an ETS domaincontaining transcription factor that forms a ternary complex transcription factor (TCF) together with ELK-1 and serum response factor accessory protein-1 (SAP-1) and binds to a specific DNA sequence through a purine-rich GGA core sequence to regulate the expression of many genes including proto-oncogenes [6,7]. Under basal conditions, ELK3 is a transcriptional repressor, which converts to a transcriptional activator in response to ratsarcoma viral oncogene homolog/ extracellular regulated protein kinases (RAS/ERK) signaling and p38 mitogen-activated protein kinase (MAPK) pathway [8][9][10], and is involved in cell migration, angiogenesis, and malignant progression [11][12][13][14]. Several studies have showed that ELK3 is overexpressed in some cancer cells and correlates with cell migration and invasion [13][14][15].…”

SMAD3 promotes ELK3 expression following transforming growth factor β‑mediated stimulation of MDA‑MB231 cells

“…ELK3 is constitutively activated in basal triple negative breast cancer cells (TNBCs) and functions as a master regulator of cancer metastasis (10,12). Previously, we suggested that the TGFβ signaling pathway is interconnected with ELK3 activity, based on the fact that ELK3 knockdown in TNBCs induces collapse of TGFβ signaling (12). In this study, we demonstrated that ELK3 is transcriptionally activated by TGFβ treatment in TNBCs.…”

“…During cancer development and progression in malignancy, the TGFβ signaling pathway acts as a tumor promotor by driving EMT, which induces tumor cell migration, invasion and ultimately metastasis to distant organs. ELK3 is constitutively activated in basal triple negative breast cancer cells (TNBCs) and functions as a master regulator of cancer metastasis (10,12). Previously, we suggested that the TGFβ signaling pathway is interconnected with ELK3 activity, based on the fact that ELK3 knockdown in TNBCs induces collapse of TGFβ signaling (12).…”

“…In line with this concept, ELK3 can be a prominent therapeutic target to prevent TGFβ-mediated metastasis of cancer cells. The potential value of ELK3 as a target of anticancer drug development is supported by the fact that TNBCs with reduced ELK3 activity completely lost their metastatic characteristics (12). It was shown that small molecule based inhibition of Ras/ERK-mediated ELK3 activity results in the inhibition of prostate cancer progression and metastasis in mice (20).…”

“…ELK3 is reported to be involved in the migration and invasion of various cancer cells including aggressive basal-like breast cancer cells and liver cancer stem cells (10,11). Previously, we reported that ELK3 suppression impairs the ability of TGFβ signaling to activate the expression of mesenchymal markers such as Vimentin, Slug and SNAIL in the triple negative breast cancer cells, which suggests that ELK3 is implicated in the TGFβ signaling pathway to regulate the metastatic process of aggressive cancer cells (12,13).…”