CYR61 confers chemoresistance by upregulating survivin expression in triple-negative breast cancer.

Cysteine-rich angiogenic inducer 61 (CYR61) is a protein from the CCN family of matricellular proteins that play diverse regulatory roles in the extracellular matrix. CYR61 is involved in cell adhesion, migration, proliferation, differentiation, apoptosis, and senescence. Here, we show that CYR61 induces chemoresistance in triple-negative breast cancer (TNBC). We observed that CYR61 is overexpressed in TNBC patients, and CYR61 expression correlates negatively with the survival of patients who receive chemotherapy. CYR61 knockdown reduced cell migration, sphere formation, and the cancer stem cell (CSC) population and increased the chemosensitivity of TNBC cells. Mechanistically, CYR61 activated Wnt/ß-catenin signaling and increased survivin expression, which are associated with chemoresistance, the epithelial-mesenchymal transition, and CSC-like phenotypes. Altogether, our study demonstrates a novel function of CYR61 in chemotherapy resistance in breast cancer.

CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer.

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.