Human breast cancer Essay

Changes in chromosomes are frequently a characteristic of aggressive signifiers of malignant neoplastic disease. In human chest malignant neoplastic disease many transforming genes and tumor suppresser cistrons and their tracts have been identified that give new possible marks for chemotherapeutic drugs. In this new survey Rab-coupling-protein ( RCP ) has been identified as a new transforming gene and possible amplicon driver in human chest malignant neoplastic disease, utilizing a new attack of microarray analysis coupled with clinical diagnosing.

In the paper by Zhang et al a new method for placing possible transforming genes has been developed ( 1 ) . This method uses a technique called TRIAGE ( triangulating transforming genes through clinico-genomic intersects ) which involves the analysis and correlativity of informations such as degrees of written text, cistron place within the genome, degree of amplified cistrons and clinical result of chest tumors, hence cistrons can be found that are amplified and overexpressed in aggressive tumor which consequence in hapless results for the patient. Using this method a high ‘score ‘ is obtained when a part is found that contains amplified and overexpressed cistrons that are present in a high figure of chest tumors. In this survey two amplicons were found, amplicons are parts of chromosomes that contain duplicates of cistrons, when this occurs within transforming genes it can do malignant neoplastic disease ; for illustration Int-2/FGF-3 cistron has been found to be amplified in chest malignant neoplastic disease and melanoma ( 2 ) . Using the Triage system the known transforming gene ERBB2, which codes for human cuticular growing factor receptor 2 ( HER2 ) on the 17q12 amplicon was identified ( 1 ) . ERBB2 is known to be involved in metastasis in chest malignant neoplastic disease and correlatives with hapless patient result ( 3 ) . This showed that the TRIAGE system successfully identifies amplicons incorporating already characterised transforming genes. Another known amplicon at the 8p11-12 part was besides identified, which is found in 10-25 % of chest tumors ( 1 ) . This amplicon contained RAB11 family-interacting protein1 ( RAB11FIP1 ) or Rab-coupling protein ( RCP ) which had non yet been identified as an transforming gene, hence this cistron was experimented on farther.

RCP in normal cells

RCP look has been antecedently shown to be involved in commanding recycling of phagosomes in macrophages ( 4 ) and besides recycling cuticular growing factor receptor ( EGFR ) and integrin a5-1 to the cell surface ( 5 ) and hence has functions in cell motility and proliferation. RCP is a matching protein which binds to Rab household little GTPases including Rab11 and Rab25 ( 6 ) . When an RCP-Rab11 composite is made, trafficking of protein receptors is switched from debasement to recycling back to the cell surface membrane ( 7 ) . Evidence of RCP being involved in cell migration and cell surface receptor recycling makes it a good campaigner transforming gene.

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RCP as an transforming gene

Zhang et Al. showed RCP overexpression, by lentiviral transfection of the RCP cistron, was capable in bring oning cancer-like belongingss in non-cancerous human mammary cells ( MCF10A ) . These belongingss included growing factor independent endurance, multilayer cell growing, increased migrational abilities and morphological alterations ensuing in cells resembling transformed fibroblasts ( 1 ) . Despite these cancer-like belongingss RCP-overexpressing MCF10A cells failed to bring on tumorigenesis when injected into non-obese diabetic severe combined immunodeficient ( NOD-SCID ) mice. RCP overexpression in established human chest malignant neoplastic disease cell lines MCF7 and MB231 resulted in a little addition in proliferation, whereas RCP knockdowns in these cells, utilizing RNA intervention, resulted in a important lessening in proliferation. These MCF7 and MB231 RCP knockdowns were so introduced into NOD-SCID mice where they caused tumorigenesis but significantly reduced metastasis when compared to controls. This shows that RCP is an of import cistron involved in cell motility and invasiveness in chest malignant neoplastic disease.

Possible oncogenic tracts

Zhang et Al. besides discovered possible tracts of RCP action. It was found that RCP overexpression resulted in enhanced extracellular-regulated kinase ( ERK ) phosphorylation in all three cell lines and when ERK phosphorylation was inhibited by U0126, RCP induced phosphorylation of ERK fell to command degrees ; in add-on cell proliferation fell to command degrees proposing that enhanced proliferation could be due to activation of the MAPK tract. Overexpression of RCP besides resulted in increased H-Ras activation in all three cell lines and in RCP knockdowns H-Ras was reduced to about undetectable degrees. Through the usage of immunoprecipitation H-Ras antibody could precipitate RCP and frailty versa demoing that both proteins may straight interact. Whether this interaction is by RCP organizing a complex with a Rab protein and triping H-Ras is unknown. Using this and other surveies affecting grounds of RCP being involved in protein recycling such as EGFR, a image of some of the possible tracts of RCP and its oncogenic effects can be hypothesised ( summarised in figure 1 ) .

‘ ( Figure 1 ) Basic flow diagram of possible consequences of RCP look demoing direct and indirect activation of H-Ras taking to ERK phosphorylation which so acts on cistrons and brings about cell proliferation. Red stars denote possible antibody suppression of RCP.

Possible marks for drugs and therapy

H-Ras activation and ERK phosphorylation are involved in the mitogen-activated protein kinase ( MAPK ) tract which consequences in cell proliferation, distinction and. Mistakes in the MAPK tract and its upstream activators such as Ras have been found to be outstanding in many malignant neoplastic diseases ( 8 ) . As ERK phosphorylation has been shown to be involved in the oncogenic consequence of RCP, drugs could be used that mark the ERK tract, one such drug is Sorafenib which is used in intervention of primary liver malignant neoplastic disease by suppressing Raf kinase taking to suppression of MEK and ERK phosphorylation in the MAPK tract ( 9 ) . The usage of an antibody binding and suppressing the map of RCP could besides be a possibility ( see figure 1 ) , in a similar manner that the chemotherapeutic antibody Trastuzumab binds to HER2 and prevents its map ( 10 ) . With possible new finds of transforming genes utilizing the TRIAGE method in other malignant neoplastic diseases, new tracts and possible curative marks could be found adding to the of all time turning complex bank of information on malignant neoplastic disease and its causes.


  • Zhang J. , Liu X. , Datta A. , Govindarajan K. , Tam W.L. , Han J. , George J. , Wong C. , Ramnarayanan K. , Phua T.Y. , Leong W.Y. , Chan Y.S. , Palanisamy N. , Liu E.T. , Karuturi K.M. , Lim B. and Miller L.D ( 2009 ) RCP is a human chest cancer-promoting cistron with Ras-activating map. The Journal of Clinical Investigation, 119, 2171-2183.
  • Uchida K. ( 2006 ) Gene elaboration and malignant neoplastic disease. Encyclopedia of Life Sciences, Published online, doi 10.1038/npg.els.0006047
  • Kauraniemi P. , Barlund M. , Monni O. , Kallioniemi A. ( 2001 ) . New Amplified and Highly Expressed Genes Discovered in the ERBB2 Amplicon in Breast Cancer by complementary DNA Microarrays. Cancer Res. 61, 8235-8240.
  • Damiani M.T. , Pavarotti M. , Leiva N. , Lindsay A.J. , McCaffrey M.W. and Colombo M.I. ( 2004 ) Rab matching protein associates with phagosomes and regulates recycling from the phagosomal compartment, Traffic, 5, 785-797.
  • Caswell P.T. , Chan M. , Lindsay A.J. , McCaffrey M.W. , Boettiger D. and Norman J.C. ( 2008 ) Rab matching protein coordinates recycling of a5-1 integrin and EGFR1 to advance cell migration in 3D microenvironments. J. Cell Biol, 183, 143-155.
  • Prekeris R. ( 2003 ) . Rabs, Rips, FIPs, and endocytic membrane traffic. Scientific World Journal, 3, 870-880.
  • Peden A.A. , Schonteich E. , Chun J. , Junutula J.R. , Scheller R.H. , Prekeris R ( 2004 ) The RCP-Rab11 complex regulates endocytic protein screening. Mol. Biol. Cell. , 15, 3530-3541.
  • Dhillon A.S. , Hagan S. , Rath O. and Kolch W. ( 2007 ) MAP kinase signalling tracts in malignant neoplastic disease. Oncogene, 26, 3279-3290.
  • Chaparro M. , Gonzalez Moreno L. , Trapero-Marugan M. , Medina J. and Moreno-Otero R. , ( 2008 ) Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other unwritten agents, Aliment. Pharmacol. Ther. 28, 1269-1277.
  • Hudis C.A. ( 2007 ) Trastuzumab – mechanism of action and usage in clinical pattern. New Engl J Med. 357, 39-51.