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Interaction between the ADAMTS-12 metalloprotease and fibulin-2 induces tumor-suppressive effects in breast cancer cells.

ABSTRACT: Balance between pro-tumor and anti-tumor effects may be affected by molecular interactions within tumor microenvironment. On this basis we searched for molecular partners of ADAMTS-12, a secreted metalloprotease that shows both oncogenic and tumor-suppressive effects. Using its spacer region as a bait in a yeast two-hybrid screen, we identified fibulin-2 as a potential ADAMTS-12-interacting protein. Fibulins are components of basement membranes and elastic matrix fibers in connective tissue. Besides this structural function, fibulins also play crucial roles in different biological events, including tumorigenesis. To examine the functional consequences of the ADAMTS-12/fibulin-2 interaction, we performed different in vitro assays using two breast cancer cell lines: the poorly invasive MCF-7 and the highly invasive MDA-MB-231. Overall our data indicate that this interaction promotes anti-tumor effects in breast cancer cells. To assess the in vivo relevance of this interaction, we induced tumors in nude mice using MCF-7 cells expressing both ADAMTS-12 and fibulin-2 that showed a remarkable growth deficiency. Additionally, we also found that ADAMTS-12 may elicit pro-tumor effects in the absence of fibulin-2. Immunohistochemical staining of breast cancer samples allowed the detection of both ADAMTS-12 and fibulin-2 in the connective tissue surrounding tumor area in less aggressive carcinomas. However, both proteins are hardly detected in more aggressive tumors. These data and survival analysis plots of breast cancer patients suggest that concomitant detection of ADAMTS-12 and fibulin-2 could be a good prognosis marker in breast cancer diagnosis.

SUBMITTER: Fontanil T

PROVIDER: S-EPMC4012729 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Interaction between the ADAMTS-12 metalloprotease and fibulin-2 induces tumor-suppressive effects in breast cancer cells.

Fontanil Tania T Rúa Susana S Llamazares María M Moncada-Pazos Angela A Quirós Pedro M PM García-Suárez Olivia O Vega Jose A JA Sasaki Takako T Mohamedi Yamina Y Esteban Manuel M MM Obaya Alvaro J AJ Cal Santiago S

Oncotarget 20140301 5

Balance between pro-tumor and anti-tumor effects may be affected by molecular interactions within tumor microenvironment. On this basis we searched for molecular partners of ADAMTS-12, a secreted metalloprotease that shows both oncogenic and tumor-suppressive effects. Using its spacer region as a bait in a yeast two-hybrid screen, we identified fibulin-2 as a potential ADAMTS-12-interacting protein. Fibulins are components of basement membranes and elastic matrix fibers in connective tissue. Bes ...[more]

PMID: 24457941

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Project description:Decremental loss of PTEN results in cancer susceptibility and tumor progression. In turn this raises the possibility that PTEN elevation might be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with variably elevated PTEN expression levels, taking advantage of BAC (Bacterial Artificial Chromosome)-mediated transgenesis. Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake, increased mitochondrial oxidative phosphorylation, and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and independent pathways, and negatively impacts two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect. In order to elucidate the pathophysiological impact of PTEN elevation, we generated transgenic mice carrying additional copies of this critical tumor suppressor gene (referred to as Super-PTEN mice). In order to maintain the regulation properties of the endogenous Pten gene, we made use of large genomic fragments containing the entire Pten locus carried by BACs (Bacterial Artificial Chromosomes). We next generated mouse embryonic fibroblasts (MEFs) and confirmed successful overexpression of PTEN by the BAC transgenic system. Primary cells derived from Super-PTEN mice represent a powerful tool to elucidate the molecular mechanisms underlying dose-dependent PTEN actions. We therefore performed microarray analysis in primary cells (MEFs) derived from day 13.5 embryos obtained by crossing Super-PTEN mice with C57BL6 mice. Three independent embryos from each genotype were analyzed (background: >98%C57BL6 / CBA). Gene expression profile analysis in these cells will reveal target genes and pathways differentially regulated upon PTEN elevation.

Dataset Information

Interaction between the ADAMTS-12 metalloprotease and fibulin-2 induces tumor-suppressive effects in breast cancer cells.

Publications

Interaction between the ADAMTS-12 metalloprotease and fibulin-2 induces tumor-suppressive effects in breast cancer cells.

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