Upregulated GATA3/miR205-5p Axis Inhibits MFNG Transcription and Reduces the Malignancy of Triple-Negative Breast Cancer

Simple Summary Triple-negative cancer (TNBC) is a deadly disease that presents a potential health threat to women worldwide. It is the most aggressive and presents a poor prognosis among all breast cancer subgroups. We previously demonstrated that the elevated expression of manic fringe (MFNG) plays a pivotal role in breast cancer. However, the mechanism through which MFNG is regulated remains obscure. The study presented here set out to determine the mechanism by which MFNG expression is regulated in TNBC. Our findings revealed that GATA3 and miR-205-p cooperatively block the transcription of MFNG leading to the inhibition of cell migration and tumor growth in vitro and in vivo. Our study uncovers a novel GATA3/miR-205-p/MFNG feed-forward loop and miR205-5p could be adopted as a potential therapeutic strategy of TNBC. Triple-negative breast cancer (TNBC) accounts for approximately 20% of all breast carcinomas and has the worst prognosis of all breast cancer subtypes due to the lack of an effective target. Therefore, understanding the molecular mechanism underpinning TNBC progression could explore a new target for therapy. While the Notch pathway is critical in the development process, its dysregulation leads to TNBC initiation. Previously, we found that manic fringe (MFNG) activates the Notch signaling and induces breast cancer progression. However, the underlying molecular mechanism of MFNG upstream remains unknown. In this study, we explore the regulatory mechanisms of MFNG in TNBC. We show that the increased expression of MFNG in TNBC is associated with poor clinical prognosis and significantly promotes cell growth and migration, as well as Notch signaling activation. The mechanistic studies reveal that MFNG is a direct target of GATA3 and miR205-5p and demonstrate that GATA3 and miR205-5p overexpression attenuate MFNG oncogenic effects, while GATA3 knockdown mimics MFNG phenotype to promote TNBC progression. Moreover, we illustrate that GATA3 is required for miR205-5p activation to inhibit MFNG transcription by binding to the 3 ' UTR region of its mRNA, which forms the GATA3/miR205-5p/MFNG feed-forward loop. Additionally, our in vivo data show that the miR205-5p mimic combined with polyetherimide-black phosphorus (PEI-BP) nanoparticle remarkably inhibits the growth of TNBC-derived tumors which lack GATA3 expression. Collectively, our study uncovers a novel GATA3/miR205-5p/MFNG feed-forward loop as a pathway that could be a potential therapeutic target for TNBC.