Xu Jinhua, Chen Yinghua, Huo Dezheng, Khramtsov Andrey, Khramtsova Galina, Zhang Chunling, Goss Kathleen H, Olopade Olufunmilayo I
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago,, Illinois.
School of Medicine, Jianghan University, Wuhan, Hubei, P. R. China.
Mol Carcinog. 2016 May;55(5):431-9. doi: 10.1002/mc.22292. Epub 2015 Feb 8.
We previously reported that the Wnt pathway is preferentially activated in basal-like breast cancer. However, the mechanisms by which the Wnt pathway regulates down-stream targets in basal-like breast cancer, and the biological significance of this regulation, are poorly understood. In this study, we found that c-Myc is highly expressed in the basal-like subtype by microarray analyses and immunohistochemical staining. After silencing β-catenin using siRNA, c-Myc expression was decreased in non-basal-like breast cancer cells. In contrast, c-Myc mRNA and protein expression were up-regulated in the basal-like breast cancer cell lines. Decreased c-Myc promoter activity was observed after inhibiting β-catenin by siRNA in non-basal-like breast cancer cells; however, inhibition of β-catenin or over-expression of dominant-negative LEF1 had no effect on c-Myc promoter activity in basal-like breast cancer cell lines. In addition, CDKN1A mRNA and p21 protein expression were significantly increased in all breast cancer cell lines upon β-catenin silencing. Interestingly, inhibiting β-catenin expression alone did not induce apoptosis in breast cancer cell lines despite c-Myc regulation, but we observed a modest increase of cells in the G1 phase of the cell cycle and decrease of cells in S phase upon β-catenin silencing. Our findings suggest that the regulation of c-Myc in breast cancer cells is dependent on the molecular subtype, and that β-catenin-mediated regulation of c-Myc and p21 may control the balance of cell death and proliferation in breast cancer.
我们之前报道过，Wnt信号通路在基底样乳腺癌中优先被激活。然而，Wnt信号通路在基底样乳腺癌中调节下游靶点的机制以及这种调节的生物学意义，目前仍知之甚少。在本研究中，我们通过微阵列分析和免疫组化染色发现，c-Myc在基底样亚型中高表达。使用小干扰RNA（siRNA）沉默β-连环蛋白后，非基底样乳腺癌细胞中的c-Myc表达降低。相反，在基底样乳腺癌细胞系中，c-Myc的mRNA和蛋白表达上调。在非基底样乳腺癌细胞中，用siRNA抑制β-连环蛋白后，观察到c-Myc启动子活性降低；然而，抑制β-连环蛋白或过表达显性负性LEF1对基底样乳腺癌细胞系中的c-Myc启动子活性没有影响。此外，在所有乳腺癌细胞系中，沉默β-连环蛋白后，CDKN1A mRNA和p21蛋白表达均显著增加。有趣的是，尽管c-Myc受到调节，但单独抑制β-连环蛋白表达并未诱导乳腺癌细胞系凋亡，但我们观察到沉默β-连环蛋白后，细胞周期的G1期细胞略有增加，S期细胞减少。我们的研究结果表明，乳腺癌细胞中c-Myc的调节取决于分子亚型，并且β-连环蛋白介导的c-Myc和p21调节可能控制乳腺癌细胞死亡和增殖的平衡。
