Experimental and Translational Oncology, Pathology, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
Bioinformatics Core Facility, Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
Cancer Res. 2021 Feb 1;81(3):594-605. doi: 10.1158/0008-5472.CAN-19-3560.
Early detection and adjuvant therapies have significantly improved survival of patients with breast cancer over the past three decades. In contrast, management of metastatic disease remains unresolved. Brain metastasis is a late complication frequently observed among patients with metastatic breast cancer, whose poor prognosis calls for novel and more effective therapies. Here, we report that active hypoxia inducible factor-1 (HIF1) signaling and loss of the miRNA concur to promote brain metastasis in a recently established model of spontaneous breast cancer metastasis from the primary site to the brain (4T1-BM), and additionally in murine and human experimental models of breast cancer brain metastasis (D2A1-BM and MDA231-BrM). Active HIF1 and let-7d loss upregulated expression of platelet-derived growth factor (PDGF) B/A in murine and human brain metastatic cells, respectively, while either individual silencing of HIF1α and PDGF-A/B or let-7d overexpression suppressed brain metastasis formation in the tested models. Let-7d silencing upregulated HIF1α expression and HIF1 activity, indicating a regulatory hierarchy of the system. The clinical relevance of the identified targets was supported by human gene expression data analyses. Treatment of mice with nilotinib, a kinase inhibitor impinging on PDGF receptor (PDGFR) signaling, prevented formation of spontaneous brain metastases in the 4T1-BM model and reduced growth of established brain metastases in mouse and human models. These results identify active HIF1 signaling and let-7d loss as coordinated events promoting breast cancer brain metastasis through increased expression of PDGF-A/B. Moreover, they identify PDGFR inhibition as a potentially actionable therapeutic strategy for patients with brain metastatis. SIGNIFICANCE: These findings show that loss of miRNA let-7d and active HIF1 signaling promotes breast cancer brain metastasis via PDGF and that pharmacologic inhibition of PDGFR suppresses brain metastasis, suggesting novel therapeutic opportunities. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/3/594/F1.large.jpg..
在过去的三十年中，早期发现和辅助治疗极大地改善了乳腺癌患者的生存率。相比之下，转移性疾病的治疗仍然没有得到解决。脑转移是转移性乳腺癌患者中经常观察到的晚期并发症，其预后不良需要新的、更有效的治疗方法。在这里，我们报告说，活性缺氧诱导因子-1（HIF1）信号和 miRNA 的缺失共同促进了自发乳腺癌转移到大脑（4T1-BM）的新建立的模型中的脑转移，并且在乳腺癌脑转移的小鼠和人类实验模型（D2A1-BM 和 MDA231-BrM）中也是如此。活性 HIF1 和 let-7d 的缺失分别上调了小鼠和人类脑转移细胞中血小板衍生生长因子（PDGF）B/A 的表达，而单独沉默 HIF1α 和 PDGF-A/B 或 let-7d 过表达均可抑制测试模型中的脑转移形成。Let-7d 的沉默上调了 HIF1α 的表达和 HIF1 的活性，表明该系统存在调控层次。所鉴定的靶标的临床相关性得到了人类基因表达数据分析的支持。用 nilotinib 治疗小鼠，一种影响血小板衍生生长因子受体（PDGFR）信号的激酶抑制剂，可防止 4T1-BM 模型中自发脑转移的形成，并减少小鼠和人类模型中已建立的脑转移的生长。这些结果表明，活性 HIF1 信号和 let-7d 的缺失通过增加 PDGF-A/B 的表达而共同促进乳腺癌脑转移。此外，它们确定了 PDGFR 抑制作为治疗脑转移患者的潜在治疗策略。意义：这些发现表明，miRNA let-7d 的缺失和活性 HIF1 信号的激活通过 PDGF 促进乳腺癌脑转移，并且 PDGFR 抑制抑制脑转移，提示新的治疗机会。
