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Mini review

Protein deregulation associated with breast cancer metastasis Ka Kui Chan a,e, Kyle B. Matchett a, Paul M. McEnhill a, El Habib Dakir a, Mary Frances McMullin a, Yahia El-Tanani a, Laurence Patterson d, Ahmed Faheem c, Philip S. Rudland b, Paul A. McCarron c, Mohamed El-Tanani d,* a

Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7BL, United Kingdom Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom School of Pharmacy and Pharmaceutical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, United Kingdom d Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire BD7 1DP, United Kingdom e Department of Pathology, The University of Hong Kong , Hong Kong Special Administrative Region b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 17 April 2015 Accepted 20 May 2015

Breast cancer is one of the most prevalent malignancies worldwide. It consists of a group of tumor cells that have the ability to grow uncontrollably, overcome replicative senescence (tumor progression) and metastasize within the body. Metastases are processes that consist of an array of complex gene dysregulation events. Although these processes are still not fully understood, the dysregulation of a number of key proteins must take place if the tumor cells are to disseminate and metastasize. It is now widely accepted that future effective and innovative treatments of cancer metastasis will have to encompass all the major components of malignant transformation. For this reason, much research is now being carried out into the mechanisms that govern the malignant transformation processes. Recent research has identified key genes involved in the development of metastases, as well as their mechanisms of action. A detailed understanding of the encoded proteins and their interrelationship generates the possibility of developing novel therapeutic approaches. This review will focus on a select group of proteins, often deregulated in breast cancer metastasis, which have shown therapeutic promise, notably, EMT, E-cadherin, Osteopontin, PEA3, Transforming Growth Factor Beta (TGF-b) and Ran. ß 2015 Elsevier Ltd. All rights reserved.

Keywords: Breast cancer metastasis EMT TGF-b Osteopontin PEA3

1. Introduction Approximately 10–15% of patients with a breast cancer diagnosis will develop distant metastases within 3 years [1]. Metastasis is initiated when tumor cells detach from the primary site and extravasate into the blood or lymph circulation (Fig. 1). The disseminated tumor cells (DTC) survive in the circulation and then intravasate and colonize new tissues by forming micrometastases and subsequent macrometastases [2]. Metastatic breast cancer is difficult to treat because, once the tumor cells spread from the original site and become DTCs, they are relatively undetectable and can remain dormant for many years after the primary tumor has been removed. Thus, it is crucial to understand the underlying mechanisms of metastasis in order to improve detection of micrometastases and develop new therapeutic agents to manage the disease. It is still elusive as to how and when these

* Corresponding author. Tel.: +44 1274 23536; fax: +44 1274 233234. E-mail address: [email protected] (M. El-Tanani).

tumor cells disseminate and migrate. Two fundamental models, known as linear progression and parallel progression, have been proposed to account for the systemic progression of a primary tumor [3–6]. In the linear progression model, as the development of the primary tumor progresses, tumor cells acquire an invasive phenotype resulting from alterations in gene expression and multiple genetic and epigenetic perturbations [7]. This resulting phenotype leads to tumor cells becoming DTC, leaving the primary site and migrating to secondary organs [8]. In contrast, the parallel progression model suggests that the metastatic founder cells appear long before the diagnosis of a primary tumor and may progress in parallel at different rates in various organs. Both models have limitations when applied to different sets of clinical data. It has been observed that the parallel progression model can account for the kinetics of metastases formation. In contrast, the commonly used tumor size (cm), local lymph node spread, distant metastatic spread (TNM) system for tumor classification can, in some instances, be explained using the linear model, particularly in instances where metastasis is associated with increasing tumor size. However, it is less accurate in other

http://dx.doi.org/10.1016/j.cytogfr.2015.05.002 1359-6101/ß 2015 Elsevier Ltd. All rights reserved.

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TGF-β Fig. 1. Integrated networks of TGF- b, osteopontin, integrin and CD44 for cell migration and invasion. OPN has a well described role in promoting metastasis. It can be mediated through interacting with TGF-b, integrin and CD44 and activated downsteam pathways. This includes the PI3 K/Akt, VGEF, C-Met and Ran GTP pathways and induces metastasis. Moreover, Smad and MEK/ERK signaling mediators of TGF-b increases cell survival and angiogenesis.

either by the intrinsic capacities of tumor cells themselves or extrinsic attractant signaling molecules released from the distant organs. The intrinsic capacity may be derived from their original cell lineages or through specific gene expression acquired upon transformation (Fig. 2), which confers the ability to interact with endothelial surface molecules of the target sites. For example, avb6 integrin on breast cancer cells interacts with laminin 5 on the basement membrane of lung capillaries as part of an

occasions, such as when the diagnosis of metastasis is at an early stage of tumor development (T1M1) [4]. An integrative and modified model of the mechanisms of metastasis may, therefore, be more useful in developing and selecting specific treatments to generate the best outcome in patients with varying breast cancer subtypes. Initial infiltration into the tissue environment of the secondary site through penetration of blood vessel endothelium can be driven

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Fig. 2. Role of osteopontin in cancer metastsis. OPN increases the activation of uPA and matrix metalloproteinases (MMPs)-mediates cell motility and invasion into the surrounding tissue. Moreover, the interaction of OPN and avb3 integrin and/or CD44-mediates cell migration, adhesion and activated endothelial cells, which are crucial during angiogenesis.

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infiltrative process into lung tissue [9–11]. This interaction subsequently facilitates some DTCs to infiltrate and survive in the local microenvironment. Bone, lung, lymph nodes and the brain represent common sites of metastatic development, regardless of the origin of the primary tumor, whereas some cancer types tend to metastasize to a specific organ [12]. In breast cancer, the typical sites of metastatic spread are usually bone and lung. The ‘‘seed and soil’’ model and the constraints of mechanical factors resulting from the anatomical structure of the vascular systems have been suggested as possible mechanisms to explain this specificity [13–16]. The change in metastatic potential may also be driven by the acquisition of genetic variations and is reflected in a specific gene expression profile (Fig. 2) [17]. For example, Minn et al. identified 95 genes that were differentially expressed in breast cancer samples that progressed to lung metastases [18]. These genes were identified through comparison with the transcriptomes between metastatic tumor cells and their matched primary tumors. The genes, which encode proteins such as epiregulin (a ligand which is specific to members of the HER/ ErbB receptor family), matrix metalloproteinase 1 and 2 (MMP-1 and MMP-2), and the cell-adhesion molecule VCAM1, have been confirmed by in vitro and in vivo experimentation to play a role in metastasis. It was also shown that activation of multiple metastasis-associated genes is required to stimulate metastatic development, such as the triplet group of CXCL, epiregulin and cyclooxygenase 2 (COX-2) [6,18,19]. The functional roles of these genes are broad and their activation during oncogenesis can confer selective advantages to various steps of metastasis, such as initiation, detachment, sustainability in the circulation, invasion of the secondary site, adaptation to the microenvironment and colonization. It is conceivable that individual cancer patients may possess a unique signature of metastasis-related gene expression patterns, which lead to varying degrees of tumor aggressiveness and metastasis. Theoretically, interference of a selection of these genes may lead to a reduction and possible termination of tumor growth. This review will describe recent developments in the understanding of breast cancer metastasis, accrued by way of detailed studies investigating novel proteins, which have been implicated in metastasis formation, their specific role, and also highlighting studies that have helped to demonstrate the mechanisms underlying the formation of organ-specific metastasis. 2. Epithelial–mesenchymal transition regulating genes The initiation of metastasis begins when select cells of the primary tumor gain enhanced motility and detach from the primary tumor through disintegration of cell–cell junctions [20]. This progression pattern is similar to the transition in which epithelial cells start acquiring mesenchymal phenotypes, that is, epithelial–mesenchymal transition (EMT), during morphogenesis [21]. The expression of this phenotype in some invasive tumor cells suggests that the genes involved in EMT, such as TWIST and SNAIL, may be involved in tumor metastasis under certain circumstances [22]. Epithelial cells normally form tight inter-cell attachments when a component part of specialized membrane structures, and gain polarity through interaction with the extracellular matrix and different adhesion molecules. Epithelial and mesenchymal cells express different sets of adhesion molecules and these expression signatures can be used as the markers for either subtype. Thus, alterations in expression levels of these adhesion molecules can lead to a change in motility and invasiveness of the tumor cells. Many of these adhesion molecules, such E-cadherin and integrins have been shown to be involved in tumor metastasis [23–27]. For example, E-cadherin is an important regulator of the epithelial phenotype and its expression has been shown to be inversely

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correlated with the progression of breast cancer and patient survival [28–30]. The N-terminus of E-cadherin mediates intercellular microfilaments via catenin [31]. Reduced expression of E-cadherin through transcriptional suppression is central to EMT in tumor progression and is accompanied with morphological changes, including the alteration of tumor cell polarity to make tumor cells become more mesenchymal-like. This change in polarity gives these cells increased motility, so that they may potentially migrate and intravasate into blood vessels, and disseminate from the primary tumor site [32,33]. The vascular endothelium is one of many barriers impeding tumor intravasation. Tumor cells need to penetrate this endothelium in order to disseminate through blood or lymphatic circulations [34]. Penetration requires an interaction between tumor cells and endothelial cells, operating in a positive feedback loop, whereby tumor cells secreting colony stimulating factor 1 (CSF-1) stimulate tumor-associated macrophages (TAMs) to release epidermal growth factor (EGF). This encourages tumor cell migration and stimulates further CSF-1 production [35], as well as the engagement of mechano- and chemico-transduction properties of the cytoskeleton of the adjacent cells [36]. The discovery of the CSF-1-TAM feedback loop is significant as CSF-1 has recently been identified as a marker for aggressiveness of in situ ductal carcinoma [37]. EMT is a dynamic process and phenotypic changes can be reversed, once the tumor cells reach the distant target sites. For example, E-cadherin suppression is thought to be transient. It has been shown that when breast tumor cells were explanted to a secondary site in vivo, this led to E-cadherin re-expression as the Ecadherin promoter became demethylated [38]. The expression of E-cadherin is regulated epigenetically and can be induced by the microenvironment of the secondary site [38]. This may explain why the expression level of E-cadherin is comparable between the primary tumor and their corresponding metastases in some findings [38,39]. Moreover, downregulation of E-cadherin can be mediated by transcriptional suppression or occasionally through mutation [40,41]. Transcriptional suppression is either accomplished by epigenetic modification or suppressed through several metastasis-associated transcription factors. Twist is a transcription factor that controls cell differentiation and, therefore, is a central mediator of morphogenesis. Twist plays an essential role that induces EMT in both development and metastasis of a tumor, through its ability to transcriptionally suppress E-cadherin [42]. Mironchik and colleagues demonstrated that more than 60% of breast tumors overexpressed Twist, whereas its expression was inversely correlated with E-cadherin levels [43,44]. These results suggested that Twist increases tumor aggressiveness by interacting with the E-cadherin promoter to suppress E-cadherin expression [45]. Twist may also play a role in promoting disseminated breast tumor cells to establish macrometastases in distant organs, Yang et al. have demonstrated that knockdown of Twist in invasive mouse mammary tumor cells resulted in a decrease in lung metastases due to less DTCs leaving the primary tumor site. This study identified Twist as an essential factor in facilitating intravasation [42]. Twist has recently been shown to have other multiple roles in inducing angiogenesis and also in promoting lung and bone metastasis through the upregulation of the macrophage chemoattractant CCL2. This increase in CCL2 leads to increased vascular permeability and further interactions with macrophages, such as those found in lung, and with osteoclasts in bone [46]. Other candidates, such as Snail and Slug, which are members of a family of zinc-finger containing transcription factors, suppress the expression of E-cadherin during metastatic progression. In addition, upregulation of these transcription factors has been observed in recurrent mammary tumors [47]. Snail and Slug have

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similar overall functions, but interact individually with a wide variety of different targets, such as genes involved in cell death, cell signaling and cell movement. Snail and Slug have been found to induce transforming growth factor beta (TGF-b) signaling through histone acetylation in the promoter region of TGF-b. In addition, TGF-b, Smad and HMGA2 have been shown to induce Snail and Slug expression [48]. Snail and Slug have also been shown recently to induce tamoxifen resistance independent of Twist via activation of the EGFR–ERK pathway in breast cancer tissue subtypes that are ER-a positive [49]. 3. Transforming growth factor-beta (TGF-b) Transforming growth factor-beta (TGF-b) is a pleiotropic cytokine that has prominent effects on cell proliferation and cell invasion [50]. It is believed that TGF-b acts as a tumor suppressor in the early phase of tumorigenesis, but then switches to promote tumor progression and metastasis [51]. This may explain the paradoxical observations whereby TGF-b exhibits an inhibitory growth effect on tumor cells, whereas it is found to be overexpressed in breast cancer, and is also correlated with malignant progression and poor prognosis [52]. TGF-b is a ligand for TGFBR1 and TGFBR2, which transduces the signal through Smad proteins. Deregulation of the TGF-b pathway in cancer can arise from mutations, transcriptional suppression or promoter hypermethylation of the Smad genes (Fig. 2) [53,54]. For metastasis, TGF-b signaling is crucial for EMT induction in tumor cells [55]. Upon stimulation, TGF-b signaling triggers the disassembly of tight junctions, desmosomes and adherens junctions [56,57]. TGF-b was shown to induce epigenetically both Snail and Twist to mediate Ecadherin downregulation. Smad3 and Smad4 form a complex with Snail, which then binds to the promoter region of the E-cadherin gene, whilst the histone methyltransferase MMSET binds to Twist [21,58]. Upon binding of TGF-b to its cognate receptor, members of the Smad family of proteins are phosphorylated and control the transcription of numerous target genes [57]. Thus, Smad proteins play a central role in TGF-b induced, EMT-associated, breast tumor progression [59,60]. Experimental results showed that TGF-b also communicates with non-Smad molecules to enhance EMT-related responses. For example, TGF-b was found to act synergistically with Ras/Raf/MEK/MAPK signaling to induce EMT. This resulted in mammary epithelial cells displaying an invasive phenotype [61]. Ras-activated MAPK has been shown to participate in TGF-b triggered Snail induction and subsequent disruption of the Ecadherin/b-catenin complex, suggesting a role of Ras signaling in EMT induction. Besides, TGF-b stimulated ERK is required to regulate the transcription of a set of genes affecting the cell motility and cell–matrix interactions in order to complete EMT [62]. TGF-b signaling also leads to the activation of the PI3K/Akt/ mTOR pathway that is involved in cell motility and invasion [58]. Activation of TGF-b signaling shares similar characteristics to those of E-cadherin, being mostly transient during tumor cell dissemination from the primary site. Once metastases are established, TGF-b signaling activity returns to basal levels to avoid causing any inhibitory growth effects on secondary tumor establishment [63]. Padua et al. showed that TGF-b in the primary tumor microenvironment primes breast cancer cells for metastasis to the lungs by increasing angiopoietin-like 4 (ANGPTL4) expression [64]. In contrast, ANGPTL4 enhances the retention of the cancer cells in the lungs, since it can disrupt the endothelial cell– cell junctions leading to an increase in the permeability of lung capillaries. Thus, it can facilitate the trans-endothelial passage of cancer cells to seed pulmonary metastases [64]. Giampieri et al. demonstrated that TGF-b modulates the mode and the route of cancer cell dissemination, where a high level of TGF-b stimulates breast cancer cells to invade in a single cell manner through Smad4

transduction [63]. This process promotes intravasation and results in blood-borne metastasis. Alternatively, low TGF-b expression favors cohesive cell motility in which metastatic cells enter the lymphatic system instead. Nevertheless, this TGF-b activity needs to be transient as constitutively overexpressed TGF-b in breast cancer cells would hinder their subsequent ability to colonize the lung. Furthermore, it has been suggested that TGF-b in the bone microenvironment is essential for the development of bone metastases in breast cancer, where osteoclastic bone resorption is the major source of TGF-b in the bone matrix [65]. This hostderived TGF-b triggers an increase in tumor production of parathyroid hormone-related protein (PTHrP) [66]. PTHrP plays a key role in bone metastasis of breast carcinoma by affecting bone resorption and osteoclastogenesis [67]. As a result, remodeling of bone structure may facilitate the DTCs to colonize the bone and form micrometastases. Overall, TGF-b plays a role in priming the breast tumor cells to metastasize to the lung and aids the invasion of tumor cells to bone. The timing of TGF-b activation, its source of production, and the mediators induced by TGF-b are carefully controlled factors necessary for the DTCs to intravasate and to form micrometastases at secondary sites. 4. Osteopontin Osteopontin (OPN) is a secreted extracellular glycophosphoprotein that can be found in different cell types, including osteoclasts, neurones, vascular smooth muscle cells, endothelial cells and breast epithelial cells [68,69]. It belongs to the small integrin binding ligand N-linked glycoprotein (SIBLING) family [70]. OPN has been linked to most of the acquired capabilities necessary for the development of malignant metastatic phenotypes (Fig. 1) [71,72]. For example, OPN can act as a growth signal regulating cell survival in both an autocrine and a paracrine manner [73,74]. This stimulatory effect not only sustains the primary tumor, but also influences the growth of metastases. It has been demonstrated that primary breast carcinomas can secrete OPN to support distant, already-established tumor cells [75]. Moreover, it has been shown that this tumor-derived OPN mediates bone marrow activation, leading to mobilization of stromal precursor cells into the systemic circulation. Once released, these precursor cells are incorporated into the metastases and differentiate into tumor-associated stromal cells [76]. The recruitment of stromal cells is important to sustain a suitable microenvironment so as to facilitate the growth of tumor cells at the secondary site [77]. Studies have also illustrated that these bone marrow-derived cells can support tumor angiogenesis, again highlighting the importance of host–tumor interaction in tumor progression [34]. Remodeling the structure of the extracellular matrix (ECM) is a prerequisite for tumor cells to acquire metastatic ability. These processes involve a series of proteolytic activities carried out by a group of enzymes known as the matrix metalloproteinases (MMPs) [78]. Members of the SIBLING family, including OPN, have the ability to bind and modulate the activity of MMPs [79]. It has been suggested that there is a distinct expression pattern associated with certain SIBLING members and MMPs in different types of cancer [70]. OPN has been shown to increase the expression and activity of MMPs and urokinase plasminogen activator (uPA) (Fig. 1), and so contribute to the migration and invasive characteristics of mammary cancer cells [80]. uPA activates a broad spectrum of MMPs and plasmin to remodel the ECM and its expression indicates a poor prognosis for breast cancer patients [81]. Moreover, the cleaved C-terminus of OPN, through the action of thrombin, can play a role in the destruction of the ECM by binding with cyclophilin C at the CD147 receptor on the cell surface, and inducing the activation of Akt and MMP-2 [82].

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Therefore, once the pioneer tumor cells detach from the primary mass and enter the blood circulation, they lose the ability to communicate with the proximal cells and the ECM, which in turn provides them with the necessary survival signals. At this stage, OPN production itself acts as an anti-apoptotic signal and can protect the cells from anoikis through the induction of anchorage independence which sustains the DTCs in the circulation [83]. Cell adhesion at the secondary site is an important process for metastasis, because it enables tumor cells to anchor before they can colonize secondary regions [84,85]. OPN may have a functional role in malignant cell attachment and invasion and it can interact with a wide range of factors, such as integrins aVb3 and the hyaluron-binding receptor, CD44 [74,86,87]. Malignant cells often have aberrant expression of integrins (Fig. 2) leading to enhanced OPN binding [88]. OPN can, therefore, act as a chemoattractant for the migration of highly metastatic breast tumor cells [89]. Moreover, a deficiency of OPN in tumor cells decreases the cells’ metastatic potential, but not their growth rate [90]. Integrin aVb3dependent interactions have also been demonstrated to be crucial for the spread of breast cancer [91]. These complex molecular interactions induce different signaling pathways, including PKC, PI3K and PLC, in breast tumorigenesis (Fig. 2) [92]. OPN signaling pathways result in gene expression alterations, which ultimately lead to alterations in tumor cell phenotypes in terms of their adhesion, migration and invasion abilities and this enhances tumor cell survival [93]. OPN is a bone matrix protein that regulates bone remodeling. It is involved in the process of mineral deposition and bone reabsorption by acting as an anchor for osteoclasts. OPN stimulates osteoclast migration by way of CD44 and aVb3, and enhances the osteoclast’s activity to resorb bone [94], while this osteoclastic bone reabsorption can facilitate vasculature formation [95]. It is believed that OPN also takes part in promoting osteolytic bone metastasis [96]. Moreover, OPN has been found to co-operate with other bone-metastasis specific genes, in breast cancer, such as Interleukin-11 (IL11) and MMP1, to increase the formation of bone metastasis. This evidence suggests that OPN plays a crucial role in modulating metastasis of breast cancer, particularly to bone. OPN is thought to have role in angiogenesis that is over and above its function as a bone modulator [97]. The mode through which OPN supports neovascularisation is three pronged; it promotes integrin-mediated endothelial cell migration, it stimulates formation of the lumen of blood vessels and it prevents apoptosis of endothelial cells through the activation of PI3K/AKT and ERK1/2 pathways [98,99]. OPN can either function in this respect via VEGF (Vascular Endothelial Growth Factor) or independently of VEGF (Fig. 2) [100]. OPN can, therefore, enhance the breast tumor expression of VEGF and subsequent neovascularisation through a paracrine mechanism. Mesenchymal stromal cells have been shown to support tumor angiogenesis. Alternatively, OPN stimulates stromal cells to transform to myofibroblasts and these myofibroblasts have been shown to promote tumor angiogenesis and mediate breast cancer metastasis [34,101]. Overexpression of OPN has been consistently implicated in highly invasive cancer cells including breast cancer cells [102]. High plasma levels of OPN are associated with a more aggressive breast tumor phenotype and shorter patient survival time [103]. Moreover, a splice variant of OPN, OPN-c, has been reported to be a more sensitive biomarker for breast cancer than HER-2, ERa and PR because this variant is undetectable in normal breast tissues [104]. Also, studies have revealed OPN has a good sensitivity and specificity for the detection of breast cancer when combined with measurement for bone sialoprotein [103]. The BRCA1 mutation, which predisposes patients to hereditary breast cancer, has also been shown to upregulate OPN in humans [105].

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5. Ran GTPase Accumulating evidence has shown that a protein called Ran GTPase acts as a pro-metastatic molecule. Ran is found in normal cells and acts as a component of the nuclear import/export complex in association with RCC1 and RanGAP [106]. This signaling pathway has been shown to act through the c-Met receptor and PI3K. Recent research has identified Ran GTPase as a novel therapeutic target in cancers that are characterized by mutations in the Myc oncogene, PI3K/Akt/mTORC1 pathway, or in the Ras/MEK/ERK cascade (Fig. 2) [106]. More specifically, shRNAmediated silencing of Ran leads to selective apoptosis of cancer cells, which have activated PI3K/Akt/mTORC1 or Ras/MEK/ERK pathways. This finding has significant potential for application in novel anti-cancer therapies, since mutations leading to activation of the PI3K/Akt/mTORC1 or Ras/MEK/ERK pathways are present in a significant number of cancers that are resistant to chemotherapy [106–108]. Resistance to targeted cancer therapies represent a significant clinical challenge, and the underlying molecular alterations leading to resistance have been identified in certain cases. For example, gefitinib resistance occurs in lung cancer due to c-Met amplification [109]. It has been found that c-Met overexpression is positively associated with gefitinib resistance and treatment with gefitinib results in a significant increase in phosphorylated c-Met (Fig. 2). When Ran was knocked down in gefitinib-resistant lung cancer cell lines, there was a significant level of apoptosis, suggesting that these lung cancer cells, despite overexpressing c-Met, were still sensitive to Ran knockdown. This sensitivity to Ran knockdown has also been identified in mutant K-Ras colon cancer cells [107]. These findings suggested that a better outcome for gefitinib-resistant lung cancer patients may be achieved if gefitinib treatment was combined with a Ran targeted therapy. An association has been identified between Ran levels and prognosis in breast cancers, where increases in Ran and Myc expression are correlated with a poorer overall prognosis [106]. Myc has been shown to upregulate Ran expression through binding to the promoter region on the Ran gene. It was also demonstrated that Ran expression could independently differentiate between breast cancer tissue samples associated with a good or poor prognosis, suggesting that Myc is not the only inducer of Ran in breast cancer [106]. 6. Polyomavirus enhancer activator 3 (Pea3) Transcription factors, other than c-Myc, that upregulate OPN have also been shown to promote cancer metastasis. For example, Pea3, which transcriptionally activates OPN expression in breast cell lines [110], has been shown to increase at the protein level in human breast cancer specimens. Pea3 belongs to the PEA3 group of transactivation domains [111] and post-translational modification of Pea3 by the MAPK pathway upregulates its transcriptional activity [112]. Moreover, Pea3 binds to the Est-responsive elements of numerous genes whose functions are associated with the invasiveness of tumor cells [113–115]. From a clinical perspective, half of the specimens of breast cancers studied show Pea3 expression [116,117]. Furthermore, the majority of cases from the HER-2/Neu positive subclass expressed high levels of Pea3, and elevated Pea3 transcriptional activity can stimulate the transcription of HER-2/ neu [118]. Elevated expression of Pea3 also correlates with a poor prognosis [119]. Moreover, overexpression of the HER-2/neu gene enhances tumor metastatic potential and induces resistance to chemotherapy [120,121]. These changes in tumor behavior may also be mediated through Pea3 as it can upregulate tumor aggressiveness [122]. In an experimental mammary model, ectopic overexpression of Pea3 in non-metastatic human breast cancer cells increased their

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invasiveness in nude mice [123]. Moreover, in a mouse model with mammary tumor virus (MMTV)-neu-induced tumors, the presence of a dominant negative form of Pea3 delayed the onset of these tumors and reduced their number and size [124]. Many in vitro studies have been undertaken to elucidate the function of Pea3. It is now generally believed that Pea3-induced tumorgenicity is mediated through the increased secretion of MMPs, such astromelysin-1 as well as type I and IV collagenases, although the precise mechanism is largely unknown [115,125]. Moreover, a novel functional role of Pea3 in tumorigenesis has recently been described, where it exerts a negative feedback loop to downregulate Cyclin D2 expression during TGF-b induced EMT, leading to increased cell migration [126]. Other proteins such as vimentin, intercellular adhesion molecule (ICAM-1) and cyclooxygenase 2, have also been reported to be upregulated by Pea3 [127–129]. Moreover, Pea3 interacts with another transcription factor, steroid receptor coactivator-1 (SRC-1), to initiate the transcription of Twist, the master regulator in EMT [42]. A recent study also indicates that Pea3-driven EMT is mediated through the Twist-related transcription factor, Snail, in which Pea-3 transcriptionally activates Snail expression [130]. Knockdown of Snail impeded the induction of EMT triggered by Pea3 overexpression in breast cancer cell lines and reduced their invasiveness. Pea3 has also been shown to upregulate OPN (Fig. 2), Twist and MMPs through interacting with transcriptional co-activators. Additionally, Pea3 itself can be upregulated via transcriptional regulation by its downstream target Cyclooxygenase-2. Pea3 has now been found to be an independent marker of prognosis in patients with breast cancer [130]. 7. Cyclooxygenase-2 (Cox-2) Cox-2 catalyzes the biosynthesis of prostaglandin H from arachidonic acid. It is an inducible enzyme that is driven by different stimuli and is involved in inflammation [131]. Overexpression of Cox-2 has been shown to occur in a number of cancer types including breast cancer [132,133]. Cox-2 expression in breast cancer is also thought to correlate with the HER-2/neu-positive subtype [134]. Furthermore, transgenic mice that possess overexpressed Cox-2 in the mammary glands produced a higher incidence of breast tumors [135]. Cox-2 inhibitors have been demonstrated to suppress the growth of breast cancer cells [132,136]. Together, these findings suggest that Cox-2 is involved in breast cancer oncogenesis. Recently, several studies have reported that Cox-2 is also involved in mediating breast cancer metastasis, especially PGE2, a downstream product of Cox2, which has been implicated in the development of bone metastases [137–141]. Upregulation of Cox2 increased the migration and invasiveness of breast cancer cells and simultaneously downregulated E-cadherin and upregulated Snail expression [142,143]. Such phenotypic changes may be mediated through an increased production of pro-urokinase plasminogen activator (pro-uPA), which can promote breakdown of the basement membrane matrix. Moreover, Cox-2 can provide a pro-inflammatory environment for breast tumor cells that activate the Akt pathway and enhance tumor progression, resulting in a poorer long-term prognosis [144]. 8. Matrix metalloproteinases (MMPs) MMPs are a group of enzymes that can modulate the extracellular matrix and have also been shown to contribute to metastasis. The substrates for MMPs are diverse, not limited to extracellular components, but also cell membrane-bound factors, which mediate different cellular signals and functions [145]. Not only do tumor cells produce MMPs, but those stromal cells surrounding the tumor cells can also act as a source. A gene signature analysis on the parental MDA-MB-231 cell line and its

lung metastasis subpopulation showed that MMP1 and MMP2 are the two genes significantly upregulated in the metastatic population of breast cancer tissue [18,146]. In the same studies, these authors demonstrated that MMP1 and MMP2, in cooperation with other metastasis-related genes, facilitate tumor angiogenesis, intravasation and vasculature remodeling, which results in the extravasation of the tumor cells from the lung capillaries into the parenchyma. Another study also illustrated that MMP13 at the breast tumor-bone interface is responsible for bone destruction and accumulation of osteoclasts [147]. This change leads to osteolytic bone metastasis, which facilitates the establishment of secondary metastasis in bone. Besides altering the local environment, MMPs also induced EMT in breast cancer cells to facilitate tumor progression. MMPs were demonstrated to downregulate E-cadherin, whereas they increased the mesenchymal marker, vimentin [36]. The signaling pathway leading to EMT is still elusive but Radisky and colleagues suggested that MMP signaling enhances Rac activity through the induction of an alternatively spliced form of Rac1, denoted Rac1b [148]. This process then triggered the generation of reactive oxygen species (ROS) and subsequently stimulated the expression of Snail, which can downregulate E-cadherin expression [148]. Moreover, MMP expression has been shown to correlate with a poor prognosis for breast cancer patients [149,150]. These findings suggest that MMPs support tumor progression and maintain breast tumorigenicity. 9. Conclusion Metastases are a significant challenge for oncologists with regards to the limitation on diagnosis and the associated mortality. Distant metastases are usually more aggressive and malignant outgrowth can cause serious complications, rendering effective therapy complicated. It is a non-random process for tumor cells to be released from the primary site and selectively colonize a distant organ. DTCs can theoretically also return to their original sites (selfseeding) and cause local recurrence [151]. It is, therefore, imperative to identify the genes involved in metastasis. These findings may provide insights into the development of more promising markers for diagnosis and therapeutic strategies. Current imaging technology is still not sensitive enough to detect single DTCs and the clinical manifestations amongst breast carcinoma are so diverse that it is difficult to apply a single, standard treatment to all patients. Therefore, it may be more rational to apply treatment related to the carcinoma gene expression signature, such as the current use of Herceptin treatment for patients who have HER-2 positive breast cancer, complemented by a thorough understanding of the molecular mechanisms regulating metastasis. Gene expression profiles and assays for specific biomarkers, such as Ran, in the primary tumors may allow prediction of the likelihood of relapse and derivation of more effective treatment regimens. So far, certain genes have been identified that may be relevant to tumor cell invasiveness and motility and are correlated with different stages of tumor progression. In this way, a comprehensive understanding of metastasis will be produced so that careful choice and validation of these molecular targets with significant potential can be rapidly translated into clinical use [151]. Through further multi-disciplinary research, a greater understanding of the molecular biology of metastasis will prime the development of increasingly effective therapeutic agents and address the ever present urgency to tackle metastatic disease. References [1] Weigelt B, Peterse JL, van’t Veer LJ. Breast cancer metastasis: markers and models. Nat. Rev. Cancer 2005;5:591–602. [2] Chambers AF, Groom AC, MacDonald CI. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2002;2(8):563–72.

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Mohamed El-Tanani, PhD Biochemistry (University of Liverpool), PGCHET (University of Bradford), Professor of Molecular Pathology and Cancer Therapeutics at University of Bradford. Over 20 years experience in Clinical Biochemistry and molecular oncology undertaking the molecular mechanism of malignant transformation, biomarker discovery and small molecule drug discovery and its mechanisms of action. Employed at King Khalid hospital (Saudi Arabia) and Alexandria University Hospital as a consultant of Clinical Biochemistry and then moved to full research posts in University of Liverpool and then moved to Queen’s University Belfast as lecturer and senior lecturer. Published over 50 papers in high profile journals with mean impact factor 7 and granted patents concerned with the discovery and development of novel biomarkers and new drugs. Act as Editor and Senior Editor for several international high profile journals.

Please cite this article in press as: Chan KK, et al. Protein deregulation associated with breast cancer metastasis. Cytokine Growth Factor Rev (2015), http://dx.doi.org/10.1016/j.cytogfr.2015.05.002