lncRNA-WAL promotes triple-negative breast cancer aggression by inducing ß-catenin nuclear translocation.

Because of its insensitivity to existing radiotherapy, namely chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/ß-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated wnt/ß-catenin pathway of TNBC tissues, lnc-WAL (wnt/ß-catenin associated lncRNA; WAL) was selected as the top upregulated lncRNA in wnt/ß-catenin pathway activation compared with the inactivation group. RIP-seq was used to compare the ß-catenin and IgG groups, where lnc-WAL could interact with ß-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted EMT, the proliferation, migration and invasion of breast cancer stem cells (BCSCs), and TNBC cells. Mechanistically, lnc-WAL inhibited ß-catenin protein degradation via Axin-mediated phosphorylation at serine 45. Subsequently, ß-catenin accumulated in the nucleus and activated the target genes. Importantly, wnt/ß-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/Axin/ß-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC. Implications: The positive feedback between lnc-WAL and the Wnt/ß-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for TNBC patients.

LncRNA ZFPM2-AS1 promotes phyllodes tumor progression by binding to CDC42 and inhibiting STAT1 activation.

Breast phyllodes tumor (PT) is a rare fibroepithelial neoplasm with potential malignant behavior. Long non-coding RNAs (lncRNAs) play multifaceted roles in various cancers, but their involvement in breast PT remains largely unexplored. In this study, microarray was leveraged for the first time to investigate the role of lncRNA in PT. We identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT, and its overexpression endowed PT with high tumor grade and adverse prognosis. Furthermore, we elucidated that ZFPM2-AS1 promotes the proliferation, migration, and invasion of malignant PT in vitro. Targeting ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft (PDX) model could effectively inhibit tumor progression in vivo. Mechanistically, our findings showed that ZFPM2-AS1 is competitively bound to CDC42, inhibiting ACK1 and STAT1 activation, thereby launching the transcription of TNFRSF19. In conclusion, our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT, and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target.