Methylpiperidino pyrazole br Introduction br Breast cancer is the most common
Breast cancer is the most common and a leading cause of death in women worldwide (Bray et al., 2018). It is a heterogeneous disease and is classified into several sub-types based on the histological markers or various gene expression profiles (Mehner et al., 2014). Despite several advances in the treatment of breast cancer, invasion and/or metastasis are one of the main causes of increased mortality. During metastasis, the cancer Methylpiperidino pyrazole evade the matrix adhesion and result in invading sur-rounding tissues or distant organs (Wu et al., 2016). The elucidation of the mechanism involved in invasion and metastasis involves a number of genes and the regulation of the expression of these genes is controlled by transcription factors (Carro et al., 2009).
One such transcription factors is E26 transformation–specific-1 (Ets-1), which has been shown to play a crucial role in carcinogenesis. It is one of the key members of the Ets transcription factor family. This fa-mily has got recognition by its well characterized DNA binding domain
(DBD), which has a helix-turn-helix motif responsible for recognizing specific DNA binding elements called Ets-binding sites that contain GGAA/T consensus sequence as the core motif (Taniguchi et al., 2007; Legrand et al., 2013). The Ets sequence was originally recognized in avian erythroblastosis retrovirus E26 and was called v-ets (viral ets) where it was transformed by viral gag/myb gene fusions. Later, a cel-lular (c) ets-1 was also found; suggesting its derivation from v-ets-1(Watson et al., 1985; Ghysdael et al., 1986). Ets-1 gene is localized on chromosome 11 in humans and acts mainly as transcriptional activator and/or repressor (Dittmer, 2015). Apart from these, Ets-1 shows its involvement in different physiological processes which include differ-entiation, proliferation, migration and apoptosis (de Nigris et al., 2001; Kita et al., 2001; Teruyama et al., 2001; Lulli et al., 2006; Higuchi et al., 2007). Regulation of Ets-1 expression is tightly controlled and its overexpression has been shown to be associated with various invasive pathologies including cancer (Redlich et al., 2001; Dittmer, 2003; Raffetseder et al., 2004). The cellular proliferation and invasion in
Abbreviations: BSA, Bovine serum albumin; ChIP, Chromatin Immunoprecipitation; EMT, Epithelial to mesenchymal transition; Ets-1, E-26 transformation-specific-1; FBS, Fetal Bovine Serum; MMPs, Matrix metalloproteinases; MMP-9, Matrix metalloproteinase-9; PBS, Phosphate Buffer Saline; PI, Protease Inhibitor; SDS PAGE, Sodium dodecayl sulphate polyacrylamide gel electrophoresis; uPA, urokinase Plasminogen Activator; WCL, Whole Cell lysate
E-mail address: [email protected] (S. Hussain).
cancer has been partly explained because of the aberrant expression of Ets-1. This invasiveness occurs because of various protease coding genes which include matrix metalloproteases such as stromelysin-1 and collagenase-1 or urokinase-type plasminogen activator (uPA) controlled by Ets-1. Therefore, in various cancers Ets-1 is currently reflected as a marker for poor prognosis (Davidson et al., 2001; Nakayama et al., 2001; Katayama et al., 2005). In addition, its role in various diseases and sharing of the same DBD in all Ets family members, Ets-1 has un-ique DNA binding affinities that favor its specific biological functions in a controlled manner and to inhibit its own DNA binding it has two inhibitory domains that flank its DBD (Lee et al., 2005).
Ets-1 transcription factor regulates the expression of matrix de-grading proteinases called matrix metalloproteinase (MMPs). These are also called matrixins and includes a family of zinc-enriched en-dopeptidases which are initially expressed as inactive pro-enzymes but due to proteolytic processing and/or degradation become active en-zymes and impart their important role in extra-cellular matrix-model-ling in development, wound healing, inflammation and cancer (Stamenkovic, 2003; Parks et al., 2004). In cancer microenvironment, MMPs play a pivotal role in the initiation, development and progression of cancer via various mechanism(s) (Kessenbrock et al., 2010; Gialeli et al., 2011). One of the key member of MMPs known to play an es-sential role in cancer is matrix metalloproteinase-9 (MMP-9), also known as gelatinase B has the potential in the degradation of two basic components of basement membrane i.e. denatured collagen and col-lagen type IV. Its overexpression pays the way for tumor progression and metastasis (Mehner et al., 2014). Strong association in the ex-pression of MMP-9 with aggressive and metastatic breast carcinogenesis has been found to be among the 70 genes in the Rosetta signature for poor prognosis of breast carcinogenesis (van 't Veer et al., 2002). Dif-ferential role of MMP-9 has been found in various processes of tumor development which include invasion, induction of angiogenesis and immunomodulation of microenvironment associated with tumor. Fur-ther, its substantial role in the creation of pre-metastatic niche that promotes colonization to other organ sites has been established (Kessenbrock et al., 2010). Higher levels of MMP-9 have been asso-ciated with increased invasiveness, metastasis and poor prognosis in cervical (Yu et al., 2009), colorectal (Zeng et al., 1996), ovarian (Sillanpaa et al., 2007) and in breast cancer (McGowan and Duffy, 2008). In addition, elevation in the expression level of MMP-9 in serum and urine has shown its association in the metastatic and prognostic analysis of a variety of tumors (Roy et al., 2009).