metastatic breast cancer metastatic breast cancer metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage iv breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. there is no cure for metastatic breast cancer; there is no stage after iv. common sites of metastasis for breast cancer metastases can occur several years after the primary breast cancer, although it is sometimes diagnosed at the same time as the primary breast cancer or, rarely, before the primary breast cancer has been diagnosed. metastatic breast cancer cells frequently differ from the preceding primary breast cancer in properties such as receptor status. the cells have often developed resistance to several lines of previous treatment and have acquired special properties that permit them to metastasize to distant sites. metastatic breast cancer can be treated, sometimes for many years, but it cannot be cured. distant metastases are the cause of about 90% of deaths due to breast cancer. breast cancer can metastasize anywhere in body but primarily metastasizes to the bone, lungs, regional lymph nodes, liver and brain, with the most common site being the bone. treatment of metastatic breast cancer depends on location of the metastatic tumors and includes surgery, radiation, chemotherapy, biological, and hormonal therapy. typical environmental barriers in a metastatic event include physical (a basement membrane), chemical (reactive oxygen species or ros, hypoxia and low ph) and biological (immune surveillance, inhibitory cytokines and regulatory extra-cellular matrix (ecm) peptides) components. organ-specific anatomic considerations also influence metastasis; these include blood-flow patterns from the primary tumor and the homing ability of cancer cells to certain tissues. the targeting by cancer cells of specific organs is probably regulated by chemo-attractant factors and adhesion molecules produced by the target organ, along with cell-surface receptors expressed by the tumor cells. symptoms the symptoms produced by metastatic breast cancer vary by the location of the metastases. for instance: metastatic disease to the bone causes severe, progressive pain, and, less commonly, pathological fracture, erythema over the affected bone, and swelling. metastatic breast cancer to the brain causes the following symptoms: persistent, progressively worsening headache, visual changes, seizures, nausea or vomiting, vertigo, behavioral and personality changes, and increased intracranial pressure. metastatic disease to the liver causes jaundice, elevated liver enzymes, abdominal pain, loss of appetite, nausea, and vomiting metastatic breast cancer to the lung or pleura causes chronic cough, dyspnea, abnormal chest x-ray, and chest pain. other nonspecific systemic symptoms of metastatic breast cancer include fatigue, malaise, weight loss, and poor appetite. sometimes people with metastatic breast cancer do not have any notable changes or symptoms. bone roughly 70% of all patients living with advanced breast cancer have bone metastases very often bone metastases can be successfully managed for a long time. brain brain metastasis is observed in 10% of breast cancer patients with metastatic properties many of the breast cancer therapies (like targeted antibodies) fail to penetrate the blood–brain barrier, hence allowing for tumor recurrence in the central nervous system. pathophysiology the main steps involved in the metastatic cascade of a cancer cell are: cell division and growth within the primary tumor invasion of the primary tumor border (basement membrane, or bm) and the tissue surrounding the tumor by the cell intravasation of the circulatory system: the cell enters the bloodstream or lymph channels. the cell must survive the transit into the new environment, until it ultimately arrests in the microvasculature of the secondary site. extravasation to a distant site : the cell then invades into the bm of the target tissue. proliferation of the cancer cell at the metastatic site formation of a micrometastasis inside the secondary site progressive colonization, forming a life-threatening metastasis the potential of a tumor cell to metastasize depends on its microenvironment, or “niche” interactions with local factors promoting tumor-cell growth, survival, angiogenesis, invasion and metastasis. this is explained by the seed and soil hypothesis. extracellular matrix degradation in cancer cell-cell and cell-ecm matrix adhesion, motility, and localised proteolysis are mediated mainly by matrix metalloproteases (mmps). degradation of the extracellular matrix begins the process of metastasis. the cell develops structures called invadopodia, which are highly concentrated in several proteases and have a highly dynamic actin cytoskeleton. mechanisms of metalloprotease action in cell motility involve: proteolytic cleavage of growth factors, so they are readily available to cells not in direct physical contact degradation of the ecm is facilitated by mmps, so cells can move across tissues into nearby stroma. regulated receptor cleavage to modulate migratory signaling most of these processes require a delicate balance between the functions of matrix metalloproteases (mmps) or metalloprotease-disintegrins (adams) and natural tissue inhibitors of metalloproteases (timps). regulated proteolysis is an important mechanism to maintain homeostasis. there is increased expression of protease systems in cancer cells, to equip them with the tools necessary to degrade the extracellular matrix and release growth factors or transmembrane receptors. mmp-2 is upregulated in the bone, and increased levels of mmp-1 and mmp-19 are observed in the brain. this in turn, upregulates the signaling pathways necessary to provide increased cell adhesion, cell motility, cell migration, invasion, cancer- cell proliferation and survival. extracellular matrix components ecm-tumor cell interactions play a critical role in each of the events of the metastatic cascade. interactions of the breast cancer cells with integrins, fibronectin, laminins, collagens, hyaluronan and proteoglycans can contribute to the metastatic process. some of these proteins are discussed here in relation to breast-cancer metastasis. fibrinogen-integrin fibronectin is an extracellular glycoprotein that can bind to integrins and other ecm components like collagen, fibrin and heparan sulphate proteoglycans(hspgs). several different integrins bind to fibronectin. fibronectin-integrin interactions are important in tumor cell migration, invasion, metastasis and cell proliferation by signaling through integrins. integrin-mediated tumor cell adhesion to ecm proteins can trigger signal transduction and cause upregulation of gene expression, increased tyrosine phosphorylytion of the focal adhesion kinase, and activation and nuclear translocation of mitogen-activated protein (map) kinases. heparanase heparanase cleaves heparin sulfate chains of hspgs, which have an extensive network with several proteins on the cell surface and ecm. the basic hspg structure consists of a protein core to which several linear heparin sulfate (hs) chains are covalently o-linked; this acts as an assembly of different ecm proteins, including fibronectin, laminins, interstitial collagens, heparin-binding growth factors, chemokines and lipoproteins. hspgs are prominent components of blood vessels. to hs stabilizes fibroblast growth factors (fgfs) and vascular endothelial growth factors (vegfs) and prevents them from inactivation. hs chains function as low-affinity co-receptors which promote dimerization of fgfs, aids in the sequestration of the growth factors (gfs) and causes activation of the signaling tyrosine kinase receptors even under low circulating concentrations of growth factors. heparanase expressed by cancer cells participates in angiogenesis and neovascularization by degrading the polysaccharide scaffold of the endothelial bm, thereby releasing angiogenic growth factors from the ecm. tenascin the ecm protein tenascin c (tnc) is up-regulated in metastatic breast cancer. tnc is an adhesion-modulating extracellular matrix glycoprotein. it is highly expressed in tumor stroma and stimulates tumor-cell proliferation. it is hypothesised that tnc stimulates invasion via up-regulation of mmp-1 expression through activation of the mapk pathway. mmp-1 (interstitial collagenase) cleaves collagen type i, ii, iii, vii and x. therefore, tenascin c over-expression can significantly alter collagen in the ecm and influence tumor cell migration in cartilaginous tissues. endoglin endoglin is a cell-surface disulfide-linked homodimeric glycoprotein which binds to integrins and other rgd ligands and is a co-receptor for tgf-beta. brain-metastatic breast-tumor cells express endoglin in large amounts. endoglin-overexpressing cells develop large numbers of invadopodia; endoglin is localized in these structures. endoglin expression in tumor cells contributes to metastasis by upregulating mmp-1 and mmp-19. mmp-19 cleaves components of the basal lamina such as collagen type iv, laminin 5, nidogen (entactin) and other ecm proteins such as tenascin, aggrecan and fibronectin. therefore, endoglin over-expression alters the proteolytic balance of the cells to greater matrix degradation and increased invasive properties of breast cancer. mechanisms in bone metastases the primary extracellular matrix components and cell-surface receptors which aid in metastasis are: integrin signalling integrin αvβ3 (a cell-surface adhesion molecule) is important for tumor attachment, cell-to-cell communication between the breast tumor cells and the environment in bone, osteoclast bone resorption and angiogenesis. integrin-mediated adhesion between cancer cells and osteoclasts in bone metastases induces phosphorylation of extracellular signal-regulated kinases (erk1/2) in osteoclasts, which in turn induces osteoclast differentiation and survival. cancer cell-blood platelet interaction metastatic breast-cancer cells excrete lysophosphatidic acid (lpa) which binds to receptors on tumor cells, inducing cell proliferation and release of cytokines(il-6 and il-8, potent bone resorptive agents) and stimulating bone resorption. after the breast-cancer cells have left the primary tumor, they interact with the bone microenvironment and secrete osteolytic factors capable of osteoclast formation and bone resorption. apart from the breast tumor cells, the resident stromal cells also contribute to tumor survival. growth factors such as epidermal growth factor (egf), fibroblast growth factor (fgf) and transforming growth factor beta (tgf-β) are implicated in the development and progression of metastatic breast cancer. matrix metalloproteinases (mmps) mmp-2 is the main metalloprotease secreted by breast-cancer cells or induced in the adjacent bone stroma; it plays an important role in the degradation of the extracellular matrix essential for metastasis. tumor cells use mmp-2 secreted by bone marrow fibroblasts (bmfs). mmp-2 is stored in an inactive conformation in association with the cell surface (or extracellular matrix) of bmfs. inactive mmp-2 present on the surface of bmfs is displaced by breast-cancer cells. cancer cells can then use the proteinase to facilitate tissue invasion, which requires the degradation of connective tissue associated with vascular basement membranes and interstitial connective tissue. mmp-2 is unlike other mmp's as its activity is modulated by metalloproteases called tissue inhibitor of metalloproteases (timp) and membrane type 1 mmp (korhmann et at. 2009) mechanism in brain metastasis the brain is a unique organ for metastasis, since the breast-tumor cells have to pass the blood–brain barrier (bbb) to form micrometastases. cd44 cd44 (a cell-surface transmembrane glycoprotein) is a receptor for hyaluronic acid, involved in cell adhesion by binding to specific extracellular matrix components. a proposed mechanism for the function of cd44 is to regulate the adhesion of circulating cancer cells in the brain to the endothelium at the secondary site with the help of a hyaluronate matrix ligand or by its cytoplasmic attachments to actin-associated proteins of the merlin/ezrin/radixin/moesin family. sialyl transferase (glycosylation modifications of gangliosides) cell-surface sialylation has been implicated in cell–to-cell interactions, and over-expression of a brain sialyltransferase in breast-cancer cells is a mechanism highlighting the role of cell-surface glycosylation in organ-specific metastatic interactions. breast-cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of bbb-crossing and brain colonization. seed and soil hypothesis the "seed and soil" hypothesis states that specific organs harbor metastases from one type of cancer by stimulating their growth better than other types of cancer. this interaction is dynamic and reciprocal, since cancer cells modify the environment they encounter. tumor embolus = seed and target organ = soil. workup in the detection of bone metastases, skeletal scintigraphy (bone scan) is very sensitive and is recommended as the first imaging study in asymptomatic individuals with suspected breast-cancer metastases. x-ray radiography is recommended if there is abnormal radionuclide uptake from the bone scan and in assessing the risk of pathological fractures, and is recommended as the initial imaging study in patients with bone pain. mri or the combination pet-ct may be considered for cases of abnormal radionuclide uptake on bone scan, when radiography does not give an acceptably clear result. treatment metastasis is a complex and interconnected multi-step process. each step in the process is a potential target for therapies to prevent or reduce metastasis. those steps which have a good clinical window are the best targets for therapy. each event in metastasis is highly regulated and requires a synergistic activation of different ecm proteins, growth factors and so on. although the occasional patient with metastatic breast cancer benefits from surgical resection of an isolated metastasis and most patients receive radiotherapy (often for palliation alone) during the course of their disease, the treatment of metastatic breast carcinoma typically involves the use of systemic therapy. there is no sufficient evidence on the benefits and risks of