Chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis promote chemoresistance by activating the NF-κB pathway in breast cancer cells.
BACKGROUND
Chemotherapy is the primary established systemic treatment for patients with breast cancer, especially those with the triple-negative subtype. Simultaneously, the resistance of triple-negative breast cancer (TNBC) to chemotherapy remains a major clinical problem. Our previous study demonstrated that the expression levels of PTN and its receptor PTPRZ1 were upregulated in recurrent TNBC tissue after chemotherapy, and this increase was closely related to poor prognosis in those patients. However, the mechanism and function of chemotherapy-driven increases in PTN/PTPRZ1 expression are still unclear.


METHODS
We compared the expression of PTN and PTPRZ1 between normal breast and cancer tissues as well as before and after chemotherapy in cancer tissue using the microarray analysis data from the GEPIA database and GEO database. The role of chemotherapy-driven increases in PTN/PTPRZ1 expression was examined with a CCK-8 assay, colony formation efficiency assay and apoptosis analysis with TNBC cells. The potential upstream pathways involved in the chemotherapy-driven increases in PTN/PTPRZ1 expression in TNBC cells were explored using microarray analysis, and the downstream mechanism was dissected with siRNA.


RESULTS
We demonstrated that the expression of PTN and PTPRZ1 was upregulated by chemotherapy, and this change in expression decreased chemosensitivity by promoting tumour proliferation and inhibiting apoptosis. CDKN1A was the critical switch that regulated the expression of PTN/PTPRZ1 in TNBC cells receiving chemotherapy. We further demonstrated that the mechanism of chemoresistance by chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis depended on the NF-κB pathway.


CONCLUSIONS
Our studies indicated that chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis play a critical role in chemoresistance, which suggests a novel strategy to enhance chemosensitivity in breast cancer cells, especially in those of the triple-negative subtype.
['Huang|Peng|P|', 'Ouyang|Deng-Jie|DJ|', 'Chang|Shi|S|', 'Li|Mo-Yun|MY|', 'Li|Lun|L|', 'Li|Qian-Ying|QY|', 'Zeng|Rong|R|', 'Zou|Qiong-Yan|QY|', 'Su|Juan|J|', 'Zhao|Piao|P|', 'Pei|Lei|L|', 'Yi|Wen-Jun|WJ|0000-0002-1563-4925']
D017209:Apoptosis D002352:Carrier Proteins D045744:Cell Line, Tumor D049109:Cell Proliferation D050759:Cyclin-Dependent Kinase Inhibitor p21 D016207:Cytokines D019008:Drug Resistance, Neoplasm D025461:Feedback, Physiological D015972:Gene Expression Regulation, Neoplastic D006801:Humans D016328:NF-kappa B D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 D015398:Signal Transduction D064726:Triple Negative Breast Neoplasms
Breast cancer Chemotherapy resistance NF-κB signalling pathway Pleiotrophin Protein tyrosine phosphatase receptor Z1