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Decreased expression of ADAMTS-1 in human breast tumors stimulates migration and invasion

Vanessa M Freitas1*, Jônatas Bussador do Amaral1, Thaiomara A Silva1, Emerson S Santos12, Flávia R Mangone3, João de Jesus Pinheiro14, Ruy G Jaeger1, Maria A Nagai3 and Gláucia Maria Machado-Santelli1

Author Affiliations

1 Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes 1524, Ed Biomédicas 1 sala 428, São Paulo, SP, 05508-000, Brazil

2 Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo Ribeirão Preto, Av. do Café, s/n, Ribeirão Preto, São Paulo, 14040-903, Brazil

3 Disciplina de Oncologia, Departamento de Radiologia e Oncologia da Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, 4 andar, São Paulo, SP, 01246-903, Brazil

4 Faculdade de Odontologia, Instituto de Ciências da Saúde, Programa de Pós-Graduação em Odontologia, Universidade Federal do Pará, Rua Augusto Corrêa, 01, Belém, Pará, 66075-110, Brazil

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Molecular Cancer 2013, 12:2  doi:10.1186/1476-4598-12-2

Published: 5 January 2013

Abstract

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.

Keywords:
ADAMTS-1; Breast cancer; Migration; Invasion; VEGF