CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer.
Seogho SonHyungjoo KimHogeun LimJoo-Hyung LeeKyung-Min LeeIncheol ShinPublished in: Cell death & disease (2023)
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC patients typically exhibit unfavorable outcomes due to its rapid growth and metastatic potential. Here, we found overexpression of CCN3 in TNBC patients. We identified that CCN3 knockdown diminished cancer stem cell formation, metastasis, and tumor growth in vitro and in vivo. Mechanistically, ablation of CCN3 reduced activity of the EGFR/MAPK pathway. Transcriptome profiling revealed that CCN3 induces glycoprotein nonmetastatic melanoma protein B (GPNMB) expression, which in turn activates the EGFR pathway. An interrogation of the TCGA dataset further supported the transcriptional regulation of GPNMB by CCN3. Finally, we showed that CCN3 activates Wnt signaling through a ligand-dependent or -independent mechanism, which increases microphthalmia-associated transcription factor (MITF) protein, a transcription factor inducing GPNMB expression. Together, our findings demonstrate the oncogenic role of CCN3 in TNBC, and we propose CCN3 as a putative therapeutic target for TNBC.
Keyphrases
- transcription factor
- small cell lung cancer
- end stage renal disease
- poor prognosis
- ejection fraction
- chronic kidney disease
- newly diagnosed
- epidermal growth factor receptor
- tyrosine kinase
- single cell
- binding protein
- cell proliferation
- gene expression
- prognostic factors
- squamous cell carcinoma
- peritoneal dialysis
- small molecule
- dna methylation
- adipose tissue
- rna seq
- protein protein
- cancer stem cells
- genome wide
- sensitive detection
- pi k akt
- quantum dots
- patient reported
- glycemic control