VGLL4 interacts with STAT3 to function as a tumor suppressor in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis, and there are no effective molecular-targeted drugs for TNBC patients in clinical practice. The JAK-STAT pathway is implicated in tumorigenesis and the progression of various cancers. In this study, the results demonstrated that VGLL4 is expressed at low levels in both TNBC specimens and cell lines and that VGLL4 expression is negatively correlated with Ki67 expression and tumor size in TNBC patients. VGLL4 knockdown can promote the growth of TNBC cells, while VGLL4 overexpression significantly suppresses the growth of TNBC cells in vitro. More importantly, VGLL4 significantly inhibits tumor progression in a nude mouse model. In addition, VGLL4 is a direct target of miR-454, and the upregulation of miR-454 decreases VGLL4 expression and promotes the cell growth of TNBC cells. Furthermore, we also demonstrated that VGLL4 interacts with STAT3, the core component of the JAK-STAT pathway, leading to the inactivation of STAT3 and the inhibition of STAT3 downstream transcription. Collectively, these findings indicate that VGLL4 expression is negatively associated with poor prognosis in TNBC patients. High expression of miR-454 may be one of the causes of the downregulation of VGLL4 in TNBC, and VGLL4 acts as a tumor suppressor in TNBC by interacting with STAT3 and subsequently suppresses the STAT3 signaling axis, providing potential biomarkers and therapeutic approaches for this fatal disease. Targeting the regulation or activity of a tumor suppressor protein that is deactivated in triple-negative breast cancer (TNBC) holds promise for the treatment of this highly aggressive form of cancer. Lin Fang and colleagues at Tongji University in Shanghai, China, showed that low levels of the protein vestigial-like family member 4 (VGLL4) promoted TNBC cell proliferation and migration, whereas overexpression of VGLL4 prevented the growth of these cells in mice. VGLL4 acts as a tumor suppressor by interfering with a signaling pathway that drives tumor growth. Furthermore, they found that VGLL4 expression is regulated by a small RNA molecule that is highly expressed in TNBC patients with poor prospects of survival. These findings provide new insights into the mechanisms underlying TNBC and highlight potential strategies for the development of targeted therapies.