Ubiquitin D Promotes Lung Metastasis by Stabilizing MMP3 in Triple-Negative Breast Cancer

TL;DR

This study shows that ubiquitin D helps breast cancer spread to the lungs by protecting a protein that breaks down tissue barriers.

Contribution

The study identifies a new regulatory pathway involving ubiquitin D, SPIB, and MMP3 in promoting metastasis in triple-negative breast cancer.

Findings

UBD stabilizes MMP3 by preventing its degradation, promoting cancer cell invasion and metastasis.

SPIB activates UBD transcription by directly binding to its promoter.

The SPIB/UBD/MMP3 axis is a key driver of lung metastasis in triple-negative breast cancer.

Abstract

Triple-negative breast cancer (TNBC) represents a notably aggressive form of breast cancer, distinguished by heightened invasiveness and an important propensity for metastasis. The expression of ubiquitin D (UBD) is significantly increased in lung metastases associated with TNBC, correlating with unfavorable patient outcomes. Functional assays indicate that UBD promotes invasion, migration, and pulmonary colonization of TNBC cells in vivo. At the mechanistic level, UBD preserves matrix metalloproteinase 3 (MMP3) levels by inhibiting proteasomal degradation. A proteomic analysis has identified MMP3 as a crucial downstream mediator of UBD. Concurrently, chromatin immunoprecipitation and luciferase reporter assays demonstrate that the Spi-B transcription factor (SPIB) directly interacts with the UBD promoter, leading to the activation of its transcription. Collectively, these findings identify the SPIB/UBD/MMP3 axis as a pivotal regulator of TNBC metastasis, indicating its value for prognostic evaluation and targeted therapy.

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