Immunoexpression of ROCK-1 and MMP-9 as prognostic markers in breast cancer
Introduction
Breast cancer is the most common cancer among women (IARC, 2012) and for 2014 there is an estimated occurrence of 57,120 new cases of breast cancer in Brazil (INCA, 2014). Despite progress in treatment with chemotherapy in patients in the early stages, there is no effective therapy for the end-stage in metastatic breast cancer. Thus, the identification of biomarkers that allow early detection of metastasis is essential for therapeutic success in the treatment of breast cancer (Fan et al., 2012).
The most common type of breast cancer is ductal carcinoma, which affects the mammary ducts and can metastasize to other locations (Germano and O’Driscoll, 2009). Tumor invasion and metastasis affect more than 90% of patients with breast cancer and are the main factors that contribute to high mortality (Moreau et al., 2007, Fagan-Solis et al., 2012). These processes occur due to the weak cytoskeletal structure allowing the low anchorage of neoplastic cells (Ortíz-López et al., 2009).
Rho-associated protein kinase 1 (ROCK-1) is among the factors that regulate cell migration and anchorage to the substrate and controls the rearrangement of the actin cytoskeleton (Ortíz-López et al., 2009). This protein plays a key role in the regulation of cell morphology, adhesion and motility (Provenzano et al., 2008) and its inhibitors are capable of reducing cancer cell migration, proliferation and invasion (Deng et al., 2010). The increased expression of ROCK-1 is related to the presence of tumor metastasis, and its inhibition is a novel approach for treating breast cancer (Liu et al., 2009).
The degradation of the extracellular matrix (ECM) is essential for the initiation and progression of tumor invasion (Wang et al., 2011), allowing the tumor cells to invade tissue, blood vessels and affecting new metastatic sites. This process is mainly influenced by the activity of matrix metalloproteinases (MMPs) that are enzymes which degrade structural components of the ECM, molecules of cell–cell and cell–ECM interactions, and activate other MMPs (Sternlicht and Werb, 2001).
MMPs can release and activate growth factors and cytokines, facilitating tumor invasion and the metastatic processes (Ellerbroek and Stack, 1999), with many human tumors characterized by increased concentrations of MMPs (Hoekstra et al., 2001). One of the major MMPs involved in breast cancer is MMP-9 (Kato et al., 2002), which is present at high levels in malignant breast tumors (Jinga et al., 2006) and related to high numbers of distant metastases (Li et al., 2004, Vizoso et al., 2007) and poor prognosis (Ranogajec et al., 2012).
The aim of the study was to estimate the prognostic value of ROCK-1 and MMP-9 proteins in women with breast cancer and to correlate them with clinicopathological parameters and overall survival. The aim was to determine their potential use in routine examinations and diagnosis and to assist in developing novel protocols to prevent development of tumor growth and metastasis.
Section snippets
Sample characterization
Tumor fragments from 60 women treated at Hospital de Base at Faculdade de Medicina de São José do Rio Preto (FAMERP) between the years 2000–2005 with a histopathological diagnosis of invasive ductal carcinoma were selected and the clinicopathological parameters were evaluated. Among the clinicopathological features, women aged over 50 years (70.0%), those who underwent surgical treatment (90.0%), chemotherapy and radiotherapy (68.3%), absence of hormone replacement therapy (68.4%) and
Results
When the expression of ROCK-1 protein in comparison to clinicopathological characteristics was correlated, higher expression was found in women with lymph node involvement compared to those without lymph nodes metastases (p = 0.007; Fig. 1a) and, observed variation in expression of ROCK-1 between different clinical tumor stages, but without a statistically significant difference (p > 0.05; Fig. 1b; Table 1). Furthermore, there were strong labeling areas of ROCK-1 protein in the group of women who
Discussion
ROCK-1 and ROCK-2 are the major kinase effector proteins of Rho GTPase signaling, correlated to the processes of invasion, angiogenesis and tumor aggressiveness (Schackmann et al., 2011). The active ROCK-1 signaling results in cell resistance to apoptosis and subsequent growth of metastatic breast lobular tumors (Schackmann et al., 2011). Tang et al. (2012) confirmed the action of ROCK-1 in the reorganization of the actin cytoskeleton, and this induces morphological alterations that are the
Acknowledgement
This study was funded by the FAPESP/Brazil – Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (2011/13154-0).
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