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  • Title: Ets-1 triggers and orchestrates the malignant phenotype of mammary cancer cells within their matrix environment.
    Author: Furlan A, Vercamer C, Desbiens X, Pourtier A.
    Journal: J Cell Physiol; 2008 Jun; 215(3):782-93. PubMed ID: 18181172.
    Abstract:
    Acquisition of invasive characteristics is a hallmark of breast carcinoma progression. During this phenomenon, Ets-1 transcription factor overexpression is induced and associated with breast cancer invasiveness, and poor prognosis. We hypothesized that Ets-1 transcription factor could be the orchestrator of a genetic program inducing the expression of genes necessary for cell motility, as postulated by the tumor microenvironment invasion model. We aimed at elucidating the role of Ets-1 in the molecular control of mammary cancer cell invasion and aggressiveness within their matrix environment. To that purpose, mouse mammary tumor MMT epithelial cells were engineered to stably overexpress Ets-1, or the dominant negative Ets-1 DNA Binding domain. The biological function of Ets-1 was assessed in three-dimensional extracellular matrix systems recreating a microenvironmental architecture resembling in vivo geometric constraints. Ets-1 overexpression provided MMT cells with a motile and invasive phenotype, leading to cell scattering, and impairing multicellular organization in matrix-mimicking gels. We evidenced that Ets-1 promoted HGF/SF activation, and the expression of its receptor, c-Met. Ets-1 also orchestrated switches in integrin expression pattern, towards a pro-migratory and malignant phenotype. Moreover, Ets-1 concomitantly triggered matrix metalloproteinases (MMP) expression and activation, thus contributing to cell scattering. Functional relevance of these observations was confirmed with blocking antibodies or MMP inhibitors. Our data highlight a critical role for Ets-1 in the orchestration of a network of molecular and phenotypic events, converging to enhance malignant features and invasion by mammary cancer cells of their environment. Ets-1 overexpression hence appears as a probable key step for breast cancer progression.
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