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.