Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors.

TitleMena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors.
Publication TypeJournal Article
Year of Publication2010
AuthorsRoussos, ET, Wang, Y, Wyckoff, JB, Sellers, RS, Wang, W, Li, J, Pollard, JW, Gertler, FB, Condeelis, JS
JournalBreast Cancer Res
Date Published2010
KeywordsAnimals, Antigens, Polyomavirus Transforming, Cytoskeletal Proteins, Disease Progression, Epidermal Growth Factor, Female, Gene Expression, Lung Neoplasms, Macrophages, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Mice, Mice, SCID, Mice, Transgenic, Neoplasm Invasiveness, Neoplasm Metastasis, Polymerase Chain Reaction, Tumor Microenvironment

INTRODUCTION: The actin binding protein Mammalian enabled (Mena), has been implicated in the metastatic progression of solid tumors in humans. Mena expression level in primary tumors is correlated with metastasis in breast, cervical, colorectal and pancreatic cancers. Cells expressing high Mena levels are part of the tumor microenvironment for metastasis (TMEM), an anatomical structure that is predictive for risk of breast cancer metastasis. Previously we have shown that forced expression of Mena adenocarcinoma cells enhances invasion and metastasis in xenograft mice. Whether Mena is required for tumor progression is still unknown. Here we report the effects of Mena deficiency on tumor progression, metastasis and on normal mammary gland development.METHODS: To investigate the role of Mena in tumor progression and metastasis, Mena deficient mice were intercrossed with mice carrying a transgene expressing the polyoma middle T oncoprotein, driven by the mouse mammary tumor virus. The progeny were investigated for the effects of Mena deficiency on tumor progression via staging of primary mammary tumors and by evaluation of morbidity. Stages of metastatic progression were investigated using an in vivo invasion assay, intravital multiphoton microscopy, circulating tumor cell burden, and lung metastases. Mammary gland development was studied in whole mount mammary glands of wild type and Mena deficient mice.RESULTS: Mena deficiency decreased morbidity and metastatic dissemination. Loss of Mena increased mammary tumor latency but had no affect on mammary tumor burden or histologic progression to carcinoma. Elimination of Mena also significantly decreased epidermal growth factor (EGF) induced in vivo invasion, in vivo motility, intravasation and metastasis. Non-tumor bearing mice deficient for Mena also showed defects in mammary gland terminal end bud formation and branching.CONCLUSIONS: Deficiency of Mena decreases metastasis by slowing tumor progression and reducing tumor cell invasion and intravasation. Mena deficiency during development causes defects in invasive processes involved in mammary gland development. These findings suggest that functional intervention targeting Mena in breast cancer patients may provide a valuable treatment option to delay tumor progression and decrease invasion and metastatic spread leading to an improved prognostic outcome.

Alternate JournalBreast Cancer Res.
PubMed ID21108830
PubMed Central IDPMC3046446
Grant ListCA100324 / CA / NCI NIH HHS / United States
CA113395 / CA / NCI NIH HHS / United States
GM58801 / GM / NIGMS NIH HHS / United States
P30CA013330 / CA / NCI NIH HHS / United States
R01 GM058801-12 / GM / NIGMS NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States
UO1CA105490 / CA / NCI NIH HHS / United States