Mechanotransduction-Induced Gene Expression Reveals Activation of TGFβ/SKIL/TAZ Axis and Supports Invasive Phenotype in Triple-Negative Breast Cancer

TL;DR

This study shows that mechanical forces in the tumor environment activate specific genes linked to cancer spread in a type of aggressive breast cancer.

Contribution

The study identifies mechanotransduction as a driver of TGFβ/SKIL/TAZ signaling and invasive traits in triple-negative breast cancer.

Findings

SKIL is the most upregulated gene in TNBC cells under mechanical strain.

TCGA data shows SKIL is highly expressed across multiple breast cancer subtypes.

Mechanical strain activates TGFβ signaling and genes linked to invasion and drug resistance.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. Emerging evidence shows that mechanotransduction, driven by matrix stiffness and mechanical signaling, promotes TNBC invasion and metastasis. As breast cancer progresses, expansion of fibroblasts and tumor-reactive stroma increases extracellular matrix deposition, generating matrix tension and enhancing mechanotransduction, which promotes cell proliferation, invasion, and metastatic potential through altered gene expression patterns. To investigate the molecular mechanisms underlying these changes, human TNBC cells were subjected to constant or oscillatory strain, followed by comprehensive transcriptomic analysis. Results revealed pronounced differential expression of genes involved in cell migration, adhesion, and transforming growth factor-β (TGFβ) signaling, with RT-PCR validation confirming SKI Like Proto Oncogene (SKIL) as the most strongly upregulated gene. Analysis of The Cancer Genome Atlas (TCGA) datasets indicated that SKIL is highly expressed in multiple breast cancer subtypes. Cross-sectional comparison of oscillatory strain-induced genes with TCGA data revealed coordinated upregulation of TGFβ, SKIL, and other genes associated with invasive phenotypes, immune suppression, and drug resistance, highlighting the vital role of TGFβ signaling. Transcription factor enrichment analysis further identified regulators linked to oncogenic pathways, including TGFβ effectors and Hippo signaling, supporting a mechanotransduction-driven transcriptional program in breast cancer.

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