Zinc and metalloproteinases 2 and 9: What is their relation with breast cancer? / Zinco e metaloproteinases 2 e 9: qual é a relação com câncer de mama?

Summary Zinc is the catalytic component of proteins that regulate responses to DNA damage, intracellular signaling enzymes, and matrix metalloproteinases, which are important proteins in carcinogenesis. The objective of this review is to bring current information on the participation of zinc and matrix metalloproteinases types 2 and 9 in mechanisms involved in the pathogenesis of breast cancer. We conducted a literature review, in consultation with the PubMed, Lilacs, and Scielo databases. The zinc and cysteine residues are structural elements shared by all members of the family of matrix metalloproteinases, and these proteins appear to be involved in the propagation of various types of neoplasms, including breast cancer. Moreover, transported zinc is likely to be used for the metalation of the catalytic domain of the newly synthesized metalloproteinases before the latter are secreted. Accordingly, increase in zinc concentrations in cellular compartments and the reduction of this trace element in the blood of patients with breast cancer appear to alter the activity of metalloproteinases 2 and 9, contributing to the occurrence of malignancy. Thus, it is necessary to carry out further studies with a view to clarify the role of zinc and metalloproteinases 2 and 9 in the pathogenesis of breast cancer.

Resumo O zinco é componente catalítico de proteínas que regulam respostas a danos no DNA, enzimas de sinalização intracelular e metaloproteinases de matriz, proteínas importantes na carcinogênese. O objetivo desta revisão é trazer informações atualizadas sobre a participação do zinco e das metaloproteinases de matriz dos tipos 2 e 9 em mecanismos envolvidos na patogênese do câncer de mama. Realizou-se um levantamento bibliográfico, mediante consulta às bases de dados PubMed, Scielo e Lilacs. O zinco e os resíduos de cisteína são elementos estruturais compartilhados por todos os membros da família das metaloproteinases de matriz, as quais parecem estar envolvidas na propagação de vários tipos de neoplasias, incluindo o câncer de mama. Além disso, é provável que o zinco transportado seja utilizado para metalação do domínio catalítico das metaloproteinases recentemente sintetizadas antes de serem segregadas. Nesse sentido, o aumento das concentrações de zinco em compartimentos celulares e a redução desse oligoelemento no sangue de pacientes com câncer de mama parecem alterar a atividade das metaloproteinases 2 e 9, contribuindo para a ocorrência de tumor maligno. Assim, faz-se necessária a realização de novos estudos na perspectiva de esclarecer o papel do zinco e das metaloproteinases 2 e 9 na patogênese do câncer de mama.

Focal Adhesion Kinase Induces Matrix Metalloproteinase-2 by Involving α5β1-Mediated Signaling in Breast Cancer Cell, MCF-7.

Introduction: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays a pivotal role in cell invasion. Matrix metalloproteinases (MMPs) are implicated as the key players in cancer cell invasion. Hence, the role of FAK in MMP regulation is very important in understanding tumor progression. Materials and Methods: Here, we studied the role of FAK, its association with other signaling kinases and involvement in the α5β1 integrin receptor-mediated regulation of MMP-2 activity and expression in human breast cancer cell line MCF-7. Results: Immuno blot analysis revealed that FN treatment causes phosphorylation of FAK and FAK gets localized at the cell attachment focal point of MCF-7 cells. FN treatment did not change the mRNA status of FAK but enhanced mRNA level of MMP-2 and MT1-MMP, also caused downregulation of TIMP-2. Co-imunoprecipitation and inhibitor studies revealed the association of FAK with α5β1, Paxillin, PI3K and ERK. siRNA studies revealed that FAK is critical in regulation of activity and expression of MMP-2 and downstream signaling kinases. Conclusion: Th e interaction of α5β1 integrin with FN initiates a signaling cascade with FAK as its central player. FAK gets phosphorylated and in turn associates with tyrosine kinases like PI3K and ERK. FAK also activates PI3K and ERK that serve as very crucial mediators of the signaling pathway leading to induction of MMP-2 activity and resulting invasion of breast cancer cell, MCF-7.

Eosinophil Inflammation of Nasal Polyp Tissue: Relationships with Matrix Metalloproteinases, Tissue Inhibitor of Metalloproteinase-1, and Transforming Growth Factor-beta1

Eosinophil and mast cell infiltrations are consistent findings in nasal polyp tissue. Previous studies have shown that matrix metalloproteinases (MMPs) may be involved in eosinophil infiltration in airway mucosa of asthmatic patients, and that transforming growth factor-beta1 (TGF-beta1) induces extracellular matrix deposition in nasal polyp tissue. The aim of this study was to evaluate the role of MMPs and tissue-inhibitor of metalloproteinase-1 (TIMP-1) in association with TGF-beta1, eosinophils and mast cell activation in nasal polyp tissue. Nasal polyp tissues from 20 patients who underwent polypectomies were collected and prepared into tissue homogenate. Eosinophil cationic protein (ECP) and tryptase levels were measured by CAP system (Pharmacia, Sweden). MMP-2, MMP-9, TIMP-1 and TGF-beta1 levels were measured by enzyme-liked immunosorbent assay. MMP-2 was the predominant form of MMPs, followed by MMP-9 and TIMP-1. There were significant correlations between ECP, and MMP-9, MMP-2, TGF-beta1 and tryptase, but not with TIMP-1. Significant correlations were noted between tryptase, and MMP-2, MMP-9, and TGF-beta1, but not with TIMP-1. Close correlations were noted between TGF-beta1, and MMP-9 and MMP-2, but not with TIMP-1. MMP-2, MMP-9, and TGF-beta1 may contribute to eosinophil and mast cell migrations into nasal polyp tissue.