Ets-1 triggers and orchestrates the malignant phenotype of mammary cancer cells within their matrix environment.
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.
Furlan
Alessandro
A
UMR-8161, Institut de Biologie de Lille, CNRS/Université de Lille-1/Université de Lille-2/Institut Pasteur de Lille, Lille Cedex, France.
Vercamer
Chantal
C
Desbiens
Xavier
X
Pourtier
Albin
A
D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism*; D005780:Gelatin / Q000378:metabolism; D005782:Gels; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D010641:Phenotype; D017434:Protein Structure, Tertiary; D050784:Proto-Oncogene Protein c-ets-1 / Q000737:chemistry / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism
D005782:Gels; D016023:Integrins; D050784:Proto-Oncogene Protein c-ets-1; D017228:Hepatocyte Growth Factor; D005780:Gelatin; D019859:Proto-Oncogene Proteins c-met