Freitas, Vanessa M.
do Amaral, Jonatas Bussador
Silva, Thaiomara A.
Santos, Emerson S.
Mangone, Flavia R.
Pinheiro, Joao de Jesus
Jaeger, Ruy G.
Nagai, Maria A.
Machado-Santelli, Glaucia Maria
Total Authors: 9
 Univ Sao Paulo, Inst Ciencias Biomed, Dept Biol Celular & Desenvolvimento, BR-05508000 Sao Paulo - Brazil
 Univ Sao Paulo Ribeirao Preto, Fac Ciencias Farmaceut, Dept Anal Clin, BR-14040903 Ribeirao Preto, SP - Brazil
 Univ Sao Paulo, Fac Med, Dept Radiol & Oncol, Disciplina Oncol, BR-01246903 Sao Paulo - Brazil
 Fed Univ Para, Fac Odontol, Inst Ciencias Saude, Programa Posgrad Odontol, BR-66075110 Belem, Para - Brazil
Total Affiliations: 4
JAN 5 2013.
Web of Science Citations:
Background: ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motifs) is a member of the ADAMTS family of metalloproteases. Here, we investigated mRNA and protein levels of ADAMTS-1 in normal and neoplastic tissues using qPCR, immunohistochemistry and immunoblot analyses, and we addressed the role of ADAMTS-1 in regulating migration, invasion and invadopodia formation in breast tumor cell lines. Results: In a series of primary breast tumors, we observed variable levels of ADAMTS-1 mRNA expression but lower levels of ADAMTS-1 protein expression in human breast cancers as compared to normal tissue, with a striking decrease observed in high-malignancy cases (triple-negative for estrogen, progesterone and Her-2). This result prompted us to analyze the effect of ADAMTS-1 knockdown in breast cancer cells in vitro. MDA-MB-231 cells with depleted ADAMTS-1 expression demonstrated increased migration, invasion and invadopodia formation. The regulatory mechanisms underlying the effects of ADAMTS-1 may be related to VEGF, a growth factor involved in migration and invasion. MDA-MB-231 cells with depleted ADAMTS-1 showed increased VEGF concentrations in conditioned medium capable of inducing human endothelial cells (HUVEC) tubulogenesis. Furthermore, expression of the VEGF receptor (VEGFR2) was increased in MDA-MB-231 cells as compared to MCF7 cells. To further determine the relationship between ADAMTS-1 and VEGF regulating breast cancer cells, MDA-MB-231 cells with reduced expression of ADAMTS-1 were pretreated with a function-blocking antibody against VEGF and then tested in migration and invasion assays; both were partially rescued to control levels. Conclusions: ADAMTS-1 expression was decreased in human breast tumors, and ADAMTS-1 knockdown stimulated migration, invasion and invadopodia formation in breast cancer cells in vitro. Therefore, this series of experiments suggests that VEGF is involved in the effects mediated by ADAMTS-1 in breast cancer cells. (AU)