University of Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000, Lille, France.
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, 01605-2324, USA.
Breast Cancer Res. 2018 Jul 11;20(1):73. doi: 10.1186/s13058-018-0992-0.
The ETS transcription factor ETV4 is involved in the main steps of organogenesis and is also a significant mediator of tumorigenesis and metastasis, such as in breast cancer. Indeed, ETV4 is overexpressed in breast tumors and is associated with distant metastasis and poor prognosis. However, the cellular and molecular events regulated by this factor are still misunderstood. In mammary epithelial cells, ETV4 controls the expression of many genes, MMP13 among them. The aim of this study was to understand the function of MMP13 during ETV4-driven tumorigenesis.
Different constructs of the MMP13 gene promoter were used to study the direct regulation of MMP13 by ETV4. Moreover, cell proliferation, migration, invasion, anchorage-independent growth, and in vivo tumorigenicity were assayed using models of mammary epithelial and cancer cells in which the expression of MMP13 and/or ETV4 is modulated. Importantly, the expression of MMP13 and ETV4 messenger RNA was characterized in 456 breast cancer samples.
Our results revealed that ETV4 promotes proliferation, migration, invasion, and anchorage-independent growth of the MMT mouse mammary tumorigenic cell line. By investigating molecular events downstream of ETV4, we found that MMP13, an extracellular metalloprotease, was an ETV4 target gene. By overexpressing or repressing MMP13, we showed that this metalloprotease contributes to proliferation, migration, and anchorage-independent clonogenicity. Furthermore, we demonstrated that MMP13 inhibition disturbs proliferation, migration, and invasion induced by ETV4 and participates to ETV4-induced tumor formation in immunodeficient mice. Finally, ETV4 and MMP13 co-overexpression is associated with poor prognosis in breast cancer.
MMP13 potentiates the effects of the ETV4 oncogene during breast cancer genesis and progression.
ETS 转录因子 ETV4 参与器官发生的主要步骤，也是肿瘤发生和转移的重要介质，如在乳腺癌中。事实上，ETV4 在乳腺癌肿瘤中过表达，并与远处转移和预后不良相关。然而，该因子调节的细胞和分子事件仍未被完全理解。在乳腺上皮细胞中，ETV4 控制着许多基因的表达，其中包括 MMP13。本研究的目的是了解 MMP13 在 ETV4 驱动的肿瘤发生过程中的作用。
使用 MMP13 基因启动子的不同构建体来研究 ETV4 对 MMP13 的直接调控。此外，通过调节 MMP13 和/或 ETV4 表达的乳腺上皮细胞和癌细胞模型，检测细胞增殖、迁移、侵袭、非锚定依赖性生长和体内肿瘤生成。重要的是，在 456 个乳腺癌样本中对 MMP13 和 ETV4 信使 RNA 的表达进行了特征分析。
我们的结果表明，ETV4 促进 MMT 小鼠乳腺肿瘤细胞系的增殖、迁移、侵袭和非锚定依赖性生长。通过研究 ETV4 下游的分子事件，我们发现细胞外金属蛋白酶 MMP13 是 ETV4 的靶基因。通过过表达或抑制 MMP13，我们表明这种金属蛋白酶有助于增殖、迁移和非锚定克隆形成。此外，我们证明 MMP13 抑制会干扰 ETV4 诱导的增殖、迁移和侵袭，并参与免疫缺陷小鼠中 ETV4 诱导的肿瘤形成。最后，ETV4 和 MMP13 的共过表达与乳腺癌的不良预后相关。
MMP13 增强了 ETV4 癌基因在乳腺癌发生和进展过程中的作用。
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