Estrogen-related receptor α promotes breast cancer cell migration and invasion by activating transforming growth factor β signaling.

Abstract

Breast cancer is a major cause of cancer-related mortality among women, and many patients eventually experience recurrence and progression to metastasis, despite advances in treatment. Estrogen-related receptor α (ERRα), an orphan nuclear receptor, is frequently overexpressed in aggressive breast cancer subtypes and is associated with poor prognosis and an increased risk of recurrence. This study aimed to investigate the role of transforming growth factor β (TGFβ) signaling in ERRα-mediated epithelial-mesenchymal transition (EMT), migration, and invasion in breast cancer cells. ERRα expression was modulated in breast cancer cells using XCT790-mediated inhibition, shRNA-mediated knockdown, and overexpression. Cell viability, clonogenicity, migration, invasion, EMT marker expression, and matrix metalloproteinase (MMP) activity were evaluated. TGFβ1 secretion and Smad signaling were also evaluated. XCT790-mediated inhibition or shRNA-mediated silencing of ERRα significantly reduced cell viability, migration, invasion, and MMP secretion in breast cancer cell lines, whereas ERRα overexpression upregulated migration, invasion, and MMP levels. ERRα suppression also upregulated the epithelial marker ZO-1 and downregulated mesenchymal markers, such as vimentin and β-catenin. This effect was associated with a significant decrease in TGFβ secretion, downregulation of TGFβ-mediated Smad signaling, and reduced expression of its downstream target ANGPTL4. These findings indicate that ERRα promotes EMT, migration, and invasion in breast cancer by upregulating TGFβ secretion and its signaling, underscoring its potential as a therapeutic target.