Funding
National Natural Science Foundation of China (NSFC)
Guangdong Science and Technology Innovation Foundation
Guangzhou Science and Technology Innovation Center (Guangdong Provincial Modern Agricultural Science and Technology Innovation Center)
ARTICLE ABSTRACT
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/β-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/β-catenin pathway of TNBC tissues, lnc-WAL (Wnt/β-catenin-associated lncRNA; WAL) was selected as the top upregulated lncRNA in Wnt/β-catenin pathway activation compared with the inactivation group. RNA immunoprecipitation sequencing was used to compare the β-catenin and IgG groups, in which lnc-WAL could interact with β-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted epithelial–mesenchymal transition, the proliferation, migration, and invasion of breast cancer stem cells and TNBC cells. Mechanistically, lnc-WAL inhibited β-catenin protein degradation via AXIN-mediated phosphorylation at serine 45. Subsequently, β-catenin accumulated in the nucleus and activated the target genes. Importantly, Wnt/β-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/AXIN/β-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/β-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for patients with TNBC.
