Tristetraprolin affects invasion‐associated genes expression and cell motility in triple‐negative breast cancer model

TL;DR

This study shows that TTP reduces cytoskeleton-related gene expression and cell motility in triple-negative breast cancer, and explores its relationship with doxorubicin treatment.

Contribution

The study reveals novel insights into TTP's role in regulating cytoskeleton genes and its potential limitations as a prognostic marker in doxorubicin-treated breast cancer patients.

Findings

Ectopic TTP expression in MDA-MB-231 cells decreases CTTN and SH3PXD2A mRNA levels and impairs cell motility.

Doxorubicin increases TTP expression and reduces cytoskeleton gene mRNA levels, but not via TTP.

High TTP expression may be a positive prognostic marker, but its interpretation is complicated in doxorubicin-treated patients.

Abstract

Tristetraprolin (TTP) is an RNA‐binding protein that negatively regulates its target mRNAs and has been shown to inhibit tumor progression and invasion. Tumor invasion requires precise regulation of cytoskeletal components, and dysregulation of cytoskeleton‐associated genes can significantly alter cell motility and invasive capability. Several genes, including SH3PXD2A, SH3PXD2B, CTTN, WIPF1, and WASL, are crucial components of the cytoskeleton reorganization machinery and are essential for adequate cell motility. These genes are also involved in invasion processes, with SH3PXD2A, SH3PXD2B, WIPF1, and CTTN being key components of invadopodia—specialized structures that facilitate invasion. However, the regulation of these genes is not well understood. This study demonstrates that ectopic expression of TTP in MDA‐MB‐231 cells leads to decreased mRNA levels of CTTN and SH3PXD2A, as well as defects in cell motility and actin filament organization. Additionally, doxorubicin significantly increases TTP expression and reduces the mRNA levels of cytoskeleton‐associated genes, enhancing our understanding of how doxorubicin may affect the transcriptional profile of cells. However, doxorubicin affects target mRNAs differently than TTP ectopic expression, suggesting it may not be the primary mechanism of doxorubicin in breast cancer (BC) treatment. High TTP expression is considered as a positive prognostic marker in multiple cancers, including BC. Given that doxorubicin is a commonly used drug for treating triple‐negative BC, using TTP as a prognostic marker in this cohort of patients might be limited since it might be challenging to understand if high TTP expression occurred due to the favorable physiological state of the patient or as a consequence of treatment.

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