Transmembrane protein 170B is a novel breast tumorigenesis suppressor gene that inhibits the Wnt/β-catenin pathway

Abstract

The identification of specific drug targets guides the development of precise cancer treatments. Compared with oncogenes, tumor suppressor genes have been poorly studied in the treatment of breast cancer. We integrate the microRNA expression array from GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) databases in clinical breast cancer tissues, and find that miR-27a is significantly upregulated and correlated with poor survival outcome and tumor progression. Transmembrane protein 170B (TMEM170B), a new functional target of miR-27a, is identified via target prediction and experimental validation, suppressing breast cancer proliferation, metastasis, and tumorigenesis. Furthermore, TMEM170B overexpression promotes cytoplasmic β-catenin phosphorylation, resulting in the inhibition of β-catenin stabilization, reduction of nuclear β-catenin levels and downstream targets expression. Clinically, TMEM170B or β-catenin expression is significantly correlated with overall survival ratio in breast cancer patients. Thus, these results highlight TMEM170B as a novel tumor suppressor target in association with the β-catenin pathway, which may provide a new therapeutic approach for human breast cancer therapy.

Antisense oligonucleotides targeting lncRNA AC104041.1 induces antitumor activity through Wnt2B/β-catenin pathway in head and neck squamous cell carcinomas

“…To our knowledge, the key switch in the canonical Wnt pathway is the protein β-catenin, upon Wnt pathway activation in the presence of Wnt ligands, the phosphorylated LRP receptor might act to directly inhibit GSK-3β and thereby promote β-catenin stabilization and nuclear accumulation 26 . Therefore, β-catenin forms an active complex with LEF (lymphoid enhancer factor) and TCF (T-cell factor) proteins 27 and activates transcription of downstream target genes including c-myc, cyclin D1, vimentin, c-jun 28 , which are the basis for tumorigenesis. Strikingly, AC104041.1 knockdown resulted in marked reduction in Wnt2B, nuclear translocation of β-catenin, c-myc, and vimentin expression, which were diminished by miR-6817-3p inhibitors (Fig.…”

Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis

“… 163 With many of Wnt ligands being able to promote the progression of breast tumors, the restoration of many Wnt inhibitors that has been silenced by mechanisms such as DNA methylation and miRNAs in tumors has effectively attenuated tumor growth. 164 , 165 , 166 Wnt pathway activation was shown to increase radiation resistance of progenitor cells in the mouse mammary gland and human breast cancer cell lines, 167 , 168 indicating that Wnt signaling is involved in resistance to current anticancer drugs potentially by regulating stem and progenitor cell populations.…”

MiR-27a: A Novel Biomarker and Potential Therapeutic Target in Tumors

“…Moreover, Li et al also reported that miR-27a could function as a suppressor in breast cancer. It targeted and down-regulated TMEM170B inhibiting the Wnt/β-catenin pathway, which could suppress breast cancer proliferation, migration, and tumorigenesis 18. Apart from the studies above which suggesting miR-27a could play a vital role in repressing many tumors growth, there were evidences illustrating that it also acted as an enhancer in the angiogenesis of tumors.…”