Breast Cancer in Women - Essay Example

? Health Sciences and Medicine, Essay   Topic Molecular Regulation of Actin Dynamics in Breast Cancer. 17th December Abstract Breast cancer is diagnosed in women worldwide and is a leading cause of breast-related mortality. Cancer cells migration is an essential stage of breast cancer metastasis. This mortality usually is associated with local invasion and metastasis rather than due to the primary cancer lesion. Identifying the factors facilitating this motility is essential in establishing the contributing factors towards cancer invasion and metastasis. Actin, a prominent protein in the cytoskeleton is highly expressed in the nucleus of normal and cancerous cells and its regulation is an important molecular event in the progression of cancer where it plays crucial roles in the cell motility and migration. It is associated in protein-protein interaction. Actin-binding proteins (ABP) are involved in the molecular regulation of actin structure and dynamics where they modulate the nucleation of new actin filament. Consequently, the activities of ABP are regulated by various signaling pathways so that there is an appropriate spatial and temporal regulation of actin dynamics in cells. The Rho-family GTPases are the most explored actin binding protein and they include RhoA which modulates the formation of contractile stress fibers. The Rac1 activates the formation of lamellipodial actin filament network at the leading edge in motile cells. Membrane phophoinositides are also involved in the regulation of actin dynamics. These molecules associate with actin binding protein ultimately regulating the activity of actin. Metastasis plays a prominent role in the pathogenesis of cancer and identification of the mechanism influencing this metastasis is essential in the development of appropriate breast cancer treatment procedures. Metastasis is a complex process encompassing different steps such as neurovascularization, stromal invasion and infiltration of cancer cells into vascular and lymphatic spaces. Introduction Breast cancer is diagnosed in women all over the world and breast cancer metastasis is a leading cause of breast-related mortality in over 90% of cancer patients’ population (Ferlay et al., 2007). Motility of cancer cells is essential in the initial stage of breast cancer metastasis. Identifying the factors facilitating this motility is essential in establishing the contributing factors towards cancer invasion and metastasis. The eukaryotic cell is made of a filamentous network of microfilaments, intermediate filaments and microtubules. This structure is collectively referred to as the cytoskeleton. The cytoplasmic network has long been associated with cell motility and proliferation but studies have shown that actin, a prominent protein in the cytoskeleton is also highly expressed in the nucleus of normal and cancerous cells (Jockusch et al., 2006). Actin cytoskeleton regulation is an important molecular event in the progression of cancer and it plays crucial roles in the cell motility and migration. Among the abundant proteins in eukaryotic cell, actin is the most abundant (Dominguez and Holmes, 2011). This protein is involved in maintaining the complex internal infrastructure of eukaryotic cells. The internal infrastructure of the cell comprises the maintenance of shape and integrity which is associated with cellular functioning. This protein forms a tangle of cross-linked filaments referred to as actin cytoskeleton that provides the organizational scaffold of animal, plant and fungal cells. In a typical cell organization, actin filaments are involved in the complex strenuous, structural tasks for instance, in the movement of myosin in muscle cells. The actin protein stricture encompasses a combination of strength and sensitivity. The actin structure can be termed as “dynamic” in virtue of their formation and roles. The dynamic model of actin is powered by a molecule of ATP which is bound to each actin monomer. Free actin bound to an ATP molecule, binds firmly to a growing actin filament whereas when the ATP is consumed and consequently the actin monomer is bound to n ADP molecule, this form is less stable and it quickly dissociates. Most structures of actin elucidated so far by methods such as crystallography have a single monomer of actin bound by actin binding protein which prevents the uncontrolled growth of actin filaments. This protein is highly conserved and is associated in protein-protein interaction. This protein exists in two forms, the monomeric (G-actin) and the filamentous state (F-actin). The occurrence of actin as either in globular or filamentous form is a state which is defined by factors such as ATP concentration, critical concentration of actin and the activity of actin binding proteins and actin-related proteins (Bettinger et al., 2004). In a normal cell, about 50% of actin is in the globular (unpolymerized) state whereas the other 50% is organized in filamentous form. These filaments are essential in the normal functioning of the cells since they are involved in formation of structural scaffolds in the cell and also act as tracks for facilitating the translocation of motor proteins and intracellular cargo (Campellone and Welch, 2010). Actin isoforms differ in a few amino acids residues usually at the N-terminal. Beta-actin is only found in non-muscle cells whereas alpha-actin is in skeletal muscles. Gamma actin is found both in muscle and non-muscle cells. To date, different structures of actin have been elucidated usually in complexes with actin-binding proteins (ABPs) and other small molecules (Dominguez and Holmes, 2011). Together with hexokinases and other forms of sugar kinases, actins constitute a structural superfamily. This structural superfamily is defined by a 375 amino acid polypeptide chain of actin folds into two major ?/? domains, commonly referred as the outer and inner domain. These two domains do not interact and the polypeptide chain passes in between them. The ATPase activity is effective in F-actin more than in the G-actin Actin Structure and Function This 48kDa protein, actin, is involved in cellular processes especially those entailing membrane dynamics. There exists a coordinated actin polymerization into actin filaments against cellular membranes, a process that propels the membrane dynamic processes (Saarikangas et al., 2009). cell migration and endocytosis are among the cellular dynamics which involve actin. For instance, in the process of cellular migration, the coordinated polymerization of actin filaments triggers plasma membrane protrusion and the advancement of the cells’ leading edge. This induction is due to the actin filaments polymerizing against the plasma membrane. On the other hand, in the process of endocytosis, the invagination which allows for the release of the cells’ vesicles involve the polymerization of actin which produces the driving force for the scission of the endocytic vesicles from the plasma membrane (Kaksonen et al., 2006). Another function of actin monomers is demonstrated in the contractile structures of the cell where together with myosin are involved in movement. For instance, the myofibrils of the muscle cells and even the stress fibers of non-muscle cells are all a combination of actin and myosin filaments. This globular protein is usually found with a nucleotide attached to the cleft between the two domains (lobes). The nucleotide may either be ADP or ATP. G-actin, the monomer form of actin assembles into polar, helical filaments under physiological conditions. Figure 1: Structures of actin and actin complexes (adapted from Dominguez and Holmes, 2011) These helical polar filaments are the F-actin. F-actin can be defined as having two structurally and biochemically distinct ends usually referred as “barbed end and pointed end.” polymerization occurs at the barbed end when the condition are optimum. However, after the hydrolysis of the attached ATP, the filament is destabilized at the pointed end (Saarikangas et al., 2009). The motile process of the cell driven by actin filaments is due to the ATP dependent polymerization at the barbed end and depolymerization at the pointed end resulting in “filament treadmilling (Pantoloni et al., 2001). Polymerization of actin starts with the formation of an aggregate of three G-actin monomers. These three G-actin monomers form the core and they are followed by addition of G-actin monomers to form the actin filaments. This polymerization process is reversible process. Figure 2: Actin dynamics; the rapidly growing actin filament barbed ends are oriented towards the plasma membrane (Saarikangas et al., 2009). Molecular Mechanism Regulating Actin Structure and Function Various proteins are involved in the regulation of actin structure and dynamics. These proteins are referred as actin-binding proteins (ABPs). These proteins may modulate the nucleation of new actin filament for instance, the Arp2/3 complex, Cobl, formins and leiomdin. Other ABPs may participate in severing actin polymerization such as gelsolin and ADF/cofilins (Ono, 2007). Apart from the functions described above, cellular organization also depends on actin with actin filament bundling and cross-linking contributing to actin mediated cellular processes. Proteins involved in these processes include ?-actinin and fascin (Cooper and Sept, 2008). Consequently, the activities of ABPs are regulated by various signaling pathways so that there is an appropriate spatial and temporal regulation of actin dynamics in cells. The Rho-family GTPases are the most explored actin binding proteins and they include RhoA which modulates the formation of contractile stress fibers. The Rac1 activates the formation of lamellipodial actin filament network at the leading edge in motile cells (Heasman and Ridley, 2008). Membrane phophoinositides are also involved in the regulation of actin dynamics. These molecules associate with actin binding protein ultimately regulating the activity of actin. Various molecules participate in the growth of actin filament. This process commences with the formation of the actin nucleus. The actin nuclease formation is catalyzed by actin filament nucleating proteins such as actin-related protein complex 2/3 which nucleates new actin filaments while remaining bound to the sides of preexisting actin filaments (Qualmann and Kessels, 2009). The actin binding protein formin is responsible for nucleating unbranched actin filaments. This results into creation of stress fibers and contractile rings. Consequently, the activity of actin nucleating proteins is further regulated by small GTPases. Cell motility is driven by rearrangement of the actin cytoskeleton both at the leading and retracting edges. Ras-like GTPases which belong to Rac/Rho family participate in modulating the actin cytoskeleton (Mackay and Hall, 1998). For instance Rac1 is involved in the formation of lamellipodia, actin-rich membrane protrusions at the cell edges (Takaishi et al., 1997). Formation of stress fibers is induced by Rho and Cdc42 is involved in actin polymerization in filopodia formation. These proteins belong to the Ras superfamily of GTPases. Cell polarity and motility are mediated by activation of Rho GTPases which facilitate the assembly of actin-myosin contractile filaments into focal adhesion complexes. According to Hakem et al., (2005), RhoC is essential in motility in metastasis of breast cancers since the loss of this protein impairs the motility of tumor cells in breast cancer. This finding has also been corroborated in a study by Kleer et al., (2002) where RhoC is over expressed in invasive breast cancers. Apart from the Rho family of GTPases, protein kinase B (PKB) has also be found to regulate actin cytoskeleton. Cancer Metastasis Breast cancer is a leading cause of mortality and morbidity among women worldwide. This mortality usually is associated with local invasion and metastasis rather than due to the primary cancer lesion (Bashyam, 2002). Metastasis plays a prominent role in the pathogenesis of breast cancer and identification of the mechanism influencing this metastasis is essential in the development of appropriate breast cancer treatment procedures. Metastasis is a complex process encompassing different steps such as neurovascularization, stromal invasion and infiltration of cancer cells into vascular and lymphatic spaces. This is followed by extravasation and the proliferation of cancer cells at a secondary site (Bashyam, 2002). This multistep process of cancer is driven by several factors, both molecular and cellular (Smith and Theodorescu, 2009). The expression of active metalloproteases (MMPs) in cancer cells is vital in facilitating cancer cells migration. Another important cellular process that is essential in breast cancer metastasis is the manipulation of actin cytoskeleton (Jang et al., 2009). Fascin is an essential protein that modulates the assembling of actin bundles into dynamic tertiary structures. These structures include microspikes, stress fibers, and membrane ruffles. Fascin over expression in normal tissues leads to membrane protrusion a key driver of cancer metastasis. Role of the Actin and Mechanism Regulating Actin Structure and Function in Cancer Metastasis Actin is an essential molecule as cell mobility is concerned. Cell migration is important in the normal functioning of the body since processes such as immune surveillance, tissue regeneration and repair. The regulation of this migration is therefore vital. Controlled spatial (space) and temporally (time) regulation of actin structures is essential in cell protrusion. Dynamic rearrangements of actin cytoskeleton are a step towards the formation of protrusive structures. These rearrangements also result in intracellular forces that drive cell translocation. In cell motility, there are two states, the polarized and non-polarized state. Cancer metastasis is driven by the abnormal modulation of cell migration, a process that involves molecular regulation of actin. Cell migration is complex multistep process which is initiated by the protrusion of the plasma membrane (Bailly and Condeelis, 2003). These protrusions have been variously termed by Yamaguchi and Condelis (2007) as filopodia, lamellipodia, invadopodia and podosomes in accordance to their morphological, structural and functional features. These structures result from the regulation of actin polymerization at the leading edge. Filopodia may be described as thin projections extending from the plasma membrane and are supported by actin filaments. The lamellipodia are broad, sheet-like membrane protrusions usually appearing at the leading edge in the cell movement whereas invadopodia are moderate broad extensions width formed by actin filaments which are cross-linked by a three-dimensional network. Invasion of the extracellular matrix is usually as a result of the formation of invadopodia. The pathology of cancer may therefore be associated with actin regulation. Several proteins mediating signaling pathways associated with regulation of actin polymerization have been reported in literature as being overexpressed in different forms of cancer (Sahai, 2005). This has been particularly evident in breast cancer related tumors. The Waskott-Aldrich syndrome protein (WASP) family proteins/Arp2/3 complex pathway has been one of the pathways studied due to its role in cell migration and invasion. Albeit there are three cytoskeleton proteins, the actin filaments, also referred as microfilaments, play the prominent role in modulating the dynamic cell motility especially in breast cancer cells (Pollard and Borisy, 2003). In cancer metastasis, tumor cells bind to transmembrane proteins referred to as integrins in discrete regions where large bundles of actin filaments (stress fibers) attach. Figure 3: Cancer cell motility; showing lamellipodia and filopodia (Jiang et al., 2009) Conclusion Metastasis is a key event in pathogenesis of most cancer because without most malignant tumors could be resectable with surgery or radiation or their combination. However in metastasis, complex signaling occurs resulting into complex cellular process that propels metastasis. Cancer metastasis is closely associated with cell migration and motility. Cell migration and motility is in turn as a result of the activity of actin cytoskeleton, a process mediated by several actin related proteins and actin binding proteins. In cancer, especially breast cancer, the main cause of pathogenesis is not as a result of the primary lesion but it is due to metastasis of cancer to critical organs where the cancerous cell proliferates in a secondary site. The movement of the cancerous site from their initial primary site is therefore as a result of the modulation of the cell framework, the actin cytoskeleton. Over expression of actin therefore is a key process in progression of breast cancer. It is imperative that more study need to be undertaken to fully establish the role of actin and the related signalling pathways that modulates actin skeleton. These studies will provide possible candidate mechanisms for development of cancer therapy aimed at preventing the spread of cancer from the initial primary sites. References Bailly, M. and Condeelis, J., 2002. Cell motility: insights from the backstage, Nat. Cell Biol., 4 E292–E294. Bashyam MD (2002) Understanding cancer metastasis: an urgent need for using differential gene expression analysis. Cancer 94:1821-1829. Bettinger, B.T., Gilbert, D.M., Amberg, D.C., 2004. Actin up in the nucleus. Nat. Rev. Mol. Cell Biol., 5: 410-415. Campellone, K.G. and Welch, M.D., 2010. 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