ETV4 transcription factor and MMP13 metalloprotease are interplaying actors of breast tumorigenesis

Abstract

BackgroundThe 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.MethodsDifferent 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.ResultsOur 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.ConclusionMMP13 potentiates the effects of the ETV4 oncogene during breast cancer genesis and progression.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0992-0) contains supplementary material, which is available to authorized users.

Knockdown of P3H4 inhibits proliferation and invasion of bladder cancer

“…Furthermore, ETV4 could regulated the P3H4 transcription in EJ and T24 cells. ETV4 (ETS Variant 4) is a transcription factor belonging to the EST family and is specifically involved in the carcinogenesis of various tissues, including pancreatic cancer, breast cancer and intestinal cancer [24][25][26]. However, little is known about the role of ETV4 in BC.…”

“…In pancreatic cancer and breast cancer, ETV4 directly upregulates the transcription of cyclin proteins, such as cyclin D1 [26] and cyclin D3 [29] to promote cell proliferation. MMPs, such as MMP13 and urokinase plasminogen activator (uPA) are also transcriptionally regulated by ETV4, which are involved in the ETV4-driven malignant phenotypes in prostate cancer [30] and breast cancer [25].…”

Identifying the Transcriptional Regulatory Network Associated With Extrathyroidal Extension in Papillary Thyroid Carcinoma by Comprehensive Bioinformatics Analysis

“…Collagen degradation is necessary for tumor invasion, and matrix metalloproteinases, which play important roles in this process, have direct causative effects on tumor progression (Page-McCaw et al, 2007;Hoffman et al, 2011;Torzilli et al, 2012). The hub gene matrix metalloproteinase 13 promotes the progression of different kinds of cancers (Dumortier et al, 2018;Liu et al, 2018). Therefore, these hub genes may promote the progression of ETE in PTC through direct or indirect interactions.…”

Overexpression of miR‑25 is associated with progression and poor prognosis of cholangiocarcinoma

“…Therefore, the prognosis of CCA patients urgently requires to be improved. A number of studies have reported that certain molecular biomarkers have crucial roles in tumor pathogenesis and development, and are highly associated with the prognosis for human malignant disease (19)(20)(21). Various prognostic biomarkers have also been identified in CCA.…”