Interaction between the ADAMTS-12 metalloprotease and fibulin-2 induces tumor-suppressive effects in breast cancer cells
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Tania Fontanil1,2,*, Susana Rúa1,2,*, María Llamazares3, Angela Moncada-Pazos4, Pedro M. Quirós1,2, Olivia García-Suárez2,5, Jose A. Vega2,5, Takako Sasaki6, Yamina Mohamedi1,2, Manuel M. Esteban7, Alvaro J. Obaya2,7 and Santiago Cal1,2
1 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Oviedo, Asturias, Spain
2 IUOPA, Instituto Universitario de Oncología del Principado de Asturias, Spain
3 German Cancer Research Center (DKFZ) Division Signal Transduction and Growth, Heidelberg, Germany
4 William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
5 Morfología y Biología Celular (grupo SINPOS), Facultad de Medicina, Universidad de Oviedo, Asturias, Spain
6 Department of Biochemistry, Faculty of Medicine, Oita University, Japan.
7 Biología Funcional, Facultad de Medicina, Universidad de Oviedo, Asturias, Spain
* These authors contributed equally to this work.
Santiago Cal, email:
Keywords: extracellular matrix, metalloprotease, ADAMTS, fibulin, breast cancer
Received: December 12, 2013 Accepted: January 12, 2014 Published: January 12, 2014
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.
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