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.

Background: Screening tumor susceptibility genes will be found powerful biomarkers for hereditary cancer monitoring, prevention and diagnosis, which providing opportunities for understanding the potential molecular mechanism and biomarker for precise treatment of hereditary cancer syndromes. Methods: Whole blood exon sequencing and bioinformatics analysis uncovers a novel RBBP8 (c.841G>T) germline mutation in this familial hereditary cancer syndrome, and verified by sanger sequencing. Cell proliferation, clone formation, cell migration, in vivo tumorigenesis were investigated by CCK8, clone formation assays, transwell, in vivo xenograft. The protein localization and interaction were detected by immunofluorescence, nuclear and cytoplasmic protein extraction kit and Co-IP. Results: A new heterozygous germline mutation of RBBP8 (c.841G>T) gene was associated with familial hereditary cancer syndrome. Unlike RBBP8-WT is mainly detected in the nucleus and could interact with BRCA1. Opposite, RBBP8(c.841G>T) is mainly located in the cytoplasm and lost interact with BRCA1, which may gain some new functions in the cytoplasm to promote breast cancer proliferation, in vivo tumorigenesis and migration. Meanwhile, patients with RBBP8(c.841G>T) germline mutation maybe benefit from PARP inhibitors (Olaparib) and platinum (Cisplatin). Conclusions: A de novo RBBP8 (c.841G>T) germline mutation was identified from familial hereditary cancer syndrome. RBBP8 (c.841G>T) lost its ability to enter the nucleus and BRCA1 binding motif, which may gain some new functions to promote tumorigeneses in the cytoplasm. RBBP8 (c.841G>T) is a tumor susceptibility gene and candidate precision medicine biomarker in this familial hereditary cancer syndrome.