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

Mandy Dumortier (1) , Franck Ladam (2) , Isabelle Damour (1) , Sophie Vacher (3) , Ivan Bieche (3) , Nathalie Marchand (1) , Yvan de Launoit (1) , David Tulasne (1, 4) , Anne Chotteau-Lelièvre (5, 1)

1 M3T - Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161
2 UMASS - University of Massachusetts Medical School [Worcester]
3 Institut Curie [Paris]
4 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
5 IBL - Institut de biologie de Lille - UMS 3702

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: MMP13 potentiates the effects of the ETV4 oncogene during breast cancer genesis and progression.

Mots clés: Breast cancer; ETV4; MMP13; Transcription factor; Tumorigenesis

Domaines: Sciences du Vivant [q-bio]

Mandy Dumortier, Franck Ladam, Isabelle Damour, Sophie Vacher, Ivan Bieche, et al.. ETV4 transcription factor and MMP13 metalloprotease are interplaying actors of breast tumorigenesis. Breast Cancer Research, 2018, 20 (1), pp.73. ⟨10.1186/s13058-018-0992-0⟩. ⟨hal-02391607⟩