de Bessa Garcia Simone Aparecida, Pavanelli Ana Carolina, Cruz E Melo Natália, Nagai Maria Aparecida
Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, São Paulo, SP 01246‑903, P.R. China.
Int J Mol Med. 2017 Apr;39(4):809-818. doi: 10.3892/ijmm.2017.2900. Epub 2017 Feb 21.
Docetaxel is an effective drug for the treatment of metastatic breast cancer. However, the exact mechanisms and/or markers associated with chemosensitivity or resistance to docetaxel remain unclear. We previously showed that the expression of prostate apoptosis response 4 (PAR4) inhibits the growth of MCF7 breast cancer cells and increases their sensitivity to docetaxel. Using cDNA microarray analysis, we evaluated transcriptome changes in MCF7 cells expressing increased levels of PAR4 and control cells before and after docetaxel treatment. Some of the top gene networks generated from the differentially expressed genes were related to the wingless‑type MMTV integration 1 (WNT) canonical (WNT/β-catenin) and non‑canonical (β‑catenin‑independent) pathways. The Human WNT signaling pathway RT2 profiler™ PCR array was used to validate the effects of PAR4 on the expression pattern of genes involved in the WNT pathway. CACNAD2A3, GDF5 and IL6 were upregulated and NANOG was downregulated in the MCF7 breast cancer cells expressing increased levels of PAR4 after treatment with docetaxel, likely indicating inactivation of the WNT/β-catenin pathway. Upregulation of FGF7, LEF1 and TWIST1 indicated activation of the WNT/β‑catenin pathway. Although preliminary, our findings could be of particular interest for understanding the action of PAR4 in chemosensitivity, particularly to increase the specificity and effectiveness of drug treatment and overcome resistance to chemotherapy. Further studies are needed to better understand the biological roles of PAR4 in the regulation of WNT pathways in breast cancer cells in response to docetaxel and other chemotherapeutic agents.
多西他赛是治疗转移性乳腺癌的一种有效药物。然而，与多西他赛化疗敏感性或耐药性相关的确切机制和/或标志物仍不清楚。我们之前表明，前列腺凋亡反应4（PAR4）的表达可抑制MCF7乳腺癌细胞的生长，并增加其对多西他赛的敏感性。我们使用cDNA微阵列分析评估了多西他赛处理前后PAR4表达水平升高的MCF7细胞和对照细胞中的转录组变化。从差异表达基因生成的一些顶级基因网络与无翅型MMTV整合1（WNT）经典（WNT/β-连环蛋白）和非经典（β-连环蛋白非依赖性）途径有关。使用人类WNT信号通路RT2 Profiler™ PCR阵列来验证PAR4对WNT途径中相关基因表达模式的影响。多西他赛处理后，PAR4表达水平升高的MCF7乳腺癌细胞中，CACNAD2A3、GDF5和IL6上调，NANOG下调，这可能表明WNT/β-连环蛋白途径失活。FGF7、LEF1和TWIST1的上调表明WNT/β-连环蛋白途径激活。尽管是初步研究，但我们的发现对于理解PAR4在化疗敏感性中的作用可能特别有意义，尤其是提高药物治疗的特异性和有效性以及克服化疗耐药性。需要进一步研究以更好地理解PAR4在乳腺癌细胞中响应多西他赛和其他化疗药物时对WNT途径调控中的生物学作用。
