The CDK6-c-Jun-Sp1-MMP-2 axis as a biomarker and therapeutic target for triple-negative breast cancer.
The CDK6-c-Jun-Sp1-MMP-2 axis as a biomarker and therapeutic target for triple-negative breast cancer.
复制标题
DOI：
--
复制
发表时间：
2020
影响因子：
5.3
通讯作者：
C. Luo;M. Hou;Chia-Wei Huang;Chun-Chieh Wu;F. Ou-Yang;Qiao-Lin Li;Cheng-Che Wu;Mei-Ren Pan
中科院分区：
文献类型：
--
作者：
C. Luo;M. Hou;Chia-Wei Huang;Chun-Chieh Wu;F. Ou-Yang;Qiao-Lin Li;Cheng-Che Wu;Mei-Ren Pan
三阴性乳腺癌(TNBC)具有高转移率、耐药率和复发率，其特点是血管生成和纤维化的微环境有利于癌症的恶性发展。然而，恶性肿瘤潜在机制的细节在很大程度上仍不清楚。我们的小鼠模型表明，与亲本细胞相比，CDK6基因的敲除显著抑制了肺转移。免疫组织化学分析显示，CDK6缺陷细胞的胶原和血管生成标记物基质金属蛋白酶-2的水平明显降低。为了研究CDK6介导的癌细胞表型的机制，我们研究了它在基质金属蛋白酶-2表达中的作用。CDK6介导c-jun和Sp1等转录因子在MMP2启动子上的募集。CDK6基因敲除可显著抑制MMP2mRNA的表达。结果显示，CDK6的表达与体外实验结果一致，分别与肿瘤血管生成和纤维连接蛋白染色的结果呈正相关。更重要的是，在筛选了31种蛋白激酶抑制剂的小分子文库后，我们发现Raf抑制剂索拉非尼在CDK6缺失的细胞中显示出最高的细胞毒性。这些数据表明，CDK6作为抗微环境靶点并影响视网膜母细胞瘤熟练患者的药物反应，提示CDK6抑制剂和索拉非尼的联合作用可能代表着TNBC患者的个性化治疗方法。
Triple-negative breast cancer (TNBC) has high metastatic, drug-resistance, and recurrence rates, and is characterized by an angiogenic and fibrotic microenvironment that favors cancer malignancy. However, details of the mechanisms underlying malignancy are still largely unknown. Our mouse model indicated that knockdown of CDK6 inhibited lung metastasis significantly compared to parental cells. Immunohistochemical analyses revealed that the levels of collagen and the angiogenic marker matrix metalloproteinase (MMP)-2 were much lower in CDK6-deficient cells. To examine mechanisms in the CDK6-mediated phenotype of cancer cells, we studied its role in MMP-2 expression. CDK6 mediated the recruitment of transcription factors including c-Jun and Sp1 to the MMP2 promoter. Knockdown of CDK6 significantly suppressed the expression of MMP2 mRNA. Consistent with the in vitro data, the expression of CDK6 was positively correlated with the angiogenic and fibrotic tumor microenvironment in TNBC patient tissues as shown by MMP-2 and fibronectin staining, respectively. More importantly, after screening a small molecule library of 31 protein kinase inhibitors, we found that the Raf inhibitor sorafenib displayed the highest cytotoxicity in CDK6-depleted cells. These data indicate that CDK6 serves as an anti-microenvironment target and affects the drug response in retinoblastoma-proficient TNBC, suggesting that combining a CDK6 inhibitor and sorafenib leads to a synthetic effect that may represent a personalized therapeutic approach for patients with TNBC.