Human breast cancer

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Alterations in chromosomes are often a characteristic of aggressive forms of cancer. In human breast cancer many oncogenes and tumour suppressor genes and their pathways have been identified that give new potential targets for chemotherapeutic drugs. In this new study Rab-coupling-protein (RCP) has been identified as a new oncogene and potential amplicon driver in human breast cancer, using a new approach of microarray analysis coupled with clinical diagnosis.

In the paper by Zhang et al a new method for identifying potential oncogenes has been developed (1). This method uses a technique called TRIAGE (triangulating oncogenes through clinico-genomic intersects) which involves the analysis and correlation of data such as levels of transcription, gene position within the genome, level of amplified genes and clinical outcome of breast tumours, therefore genes can be found that are amplified and overexpressed in aggressive tumours which result in poor outcomes for the patient. Using this method a high 'score' is obtained when a region is found that contains amplified and overexpressed genes that are present in a high number of breast tumours. In this study two amplicons were found, amplicons are regions of chromosomes that contain duplications of genes, when this occurs within oncogenes it can cause cancer; for example Int-2/FGF-3 gene has been found to be amplified in breast cancer and melanoma (2). Using the TRIAGE system the known oncogene ERBB2, which codes for human epidermal growth factor receptor 2 (HER2) on the 17q12 amplicon was identified (1). ERBB2 is known to be involved in metastasis in breast cancer and correlates with poor patient outcome (3). This showed that the TRIAGE system successfully identifies amplicons containing already characterised oncogenes. Another known amplicon at the 8p11-12 region was also identified, which is found in 10-25% of breast tumours (1). This amplicon contained RAB11 family-interacting protein1 (RAB11FIP1) or Rab-coupling protein (RCP) which had not yet been identified as an oncogene, therefore this gene was experimented on further.

RCP in normal cells

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RCP expression has been previously shown to be involved in controlling recycling of phagosomes in macrophages (4) and also recycling epidermal growth factor receptor (EGFR) and integrin a5-1 to the cell surface (5) and therefore has roles in cell motility and proliferation. RCP is a coupling protein which binds to Rab family small GTPases including Rab11 and Rab25 (6). When an RCP-Rab11 complex is made, trafficking of protein receptors is switched from degradation 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 candidate oncogene.

RCP as an oncogene

Zhang et al. showed RCP overexpression, by lentiviral transfection of the RCP gene, was capable in inducing cancer-like properties in non-cancerous human mammary cells (MCF10A). These properties included growth factor independent survival, multilayer cell growth, increased migrational abilities and morphological changes resulting in cells resembling transformed fibroblasts (1). Despite these cancer-like properties RCP-overexpressing MCF10A cells failed to induce tumorigenesis when injected into non-obese diabetic severe combined immunodeficient (NOD-SCID) mice. RCP overexpression in established human breast cancer cell lines MCF7 and MB231 resulted in a small increase in proliferation, whereas RCP knockdowns in these cells, using RNA interference, resulted in a significant decrease in proliferation. These MCF7 and MB231 RCP knockdowns were then introduced into NOD-SCID mice where they caused tumorigenesis but significantly reduced metastasis when compared to controls. This shows that RCP is an important gene involved in cell motility and invasiveness in breast cancer.

Possible oncogenic pathways

Zhang et al. also discovered possible pathways 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 control levels; in addition cell proliferation fell to control levels suggesting that enhanced proliferation could be due to activation of the MAPK pathway. Overexpression of RCP also resulted in increased H-Ras activation in all three cell lines and in RCP knockdowns H-Ras was reduced to almost undetectable levels. Through the use of immunoprecipitation H-Ras antibody could precipitate RCP and vice versa showing that both proteins may directly interact. Whether this interaction is by RCP forming a complex with a Rab protein and activating H-Ras is unknown. Using this and other studies involving evidence of RCP being involved in protein recycling such as EGFR, a picture of some of the possible pathways of RCP and its oncogenic effects can be hypothesised (summarised in figure 1).

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'(Figure 1) Basic flow diagram of possible results of RCP expression showing direct and indirect activation of H-Ras leading to ERK phosphorylation which then acts on genes and brings about cell proliferation. Red stars denote possible antibody inhibition of RCP.

Possible targets for drugs and therapy

H-Ras activation and ERK phosphorylation are involved in the mitogen-activated protein kinase (MAPK) pathway which results in cell proliferation, differentiation and . Faults in the MAPK pathway and its upstream activators such as Ras have been found to be prominent in many cancers (8). As ERK phosphorylation has been shown to be involved in the oncogenic effect of RCP, drugs could be used that target the ERK pathway, one such drug is Sorafenib which is used in treatment of primary liver cancer by inhibiting Raf kinase leading to inhibition of MEK and ERK phosphorylation in the MAPK pathway (9). The use of an antibody binding and inhibiting the function of RCP could also be a possibility (see figure 1), in a similar way that the chemotherapeutic antibody Trastuzumab binds to HER2 and prevents its function (10). With possible new discoveries of oncogenes using the TRIAGE method in other cancers, new pathways and potential therapeutic targets could be found adding to the ever growing complex bank of information on cancer and its causes.

References:

  • 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 breast cancer-promoting gene with Ras-activating function. The Journal of Clinical Investigation, 119, 2171-2183.
  • Uchida K. (2006) Gene amplification and cancer. Encyclopedia of Life Sciences, Published online, doi 10.1038/npg.els.0006047
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  • Damiani M.T., Pavarotti M., Leiva N., Lindsay A.J., McCaffrey M.W. and Colombo M.I. (2004) Rab coupling 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 coupling protein coordinates recycling of a5-1 integrin and EGFR1 to promote cell migration in 3D microenvironments. J. Cell Biol, 183, 143-155.
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