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

Author(s)

Freitas, Vanessa M. ^[1] ; do Amaral, Jonatas Bussador ^[1] ; Silva, Thaiomara A. ^[1] ; Santos, Emerson S. ^{[1, 2]} ; Mangone, Flavia R. ^[3] ; Pinheiro, Joao de Jesus ^{[1, 4]} ; Jaeger, Ruy G. ^[1] ; Nagai, Maria A. ^[3] ; Machado-Santelli, Glaucia Maria ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Biol Celular & Desenvolvimento, BR-05508000 Sao Paulo - Brazil

^[2] Univ Sao Paulo Ribeirao Preto, Fac Ciencias Farmaceut, Dept Anal Clin, BR-14040903 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Fac Med, Dept Radiol & Oncol, Disciplina Oncol, BR-01246903 Sao Paulo - Brazil

^[4] Fed Univ Para, Fac Odontol, Inst Ciencias Saude, Programa Posgrad Odontol, BR-66075110 Belem, Para - Brazil

• Document type: Journal article
• Source: Molecular Cancer; v. 12, JAN 5 2013.
• Web of Science Citations: 25

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. (AU)

• FAPESP's process: 06/01026-0 - Functional characterization of genes potentially regulated by estrogen receptor and/or ERBB2 oncogene: implications in the diagnosis, prognosis and treatment of breast cancer
• Grantee: Maria Aparecida Nagai
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/07699-1 - Protease ADAMTS1 influencing breast cancer behavior and microenvironment
• Grantee: Vanessa Morais Freitas
• Support Opportunities: Research Grants - Young Investigators Grants