AIMS--To assess whether the overexpression of five dominant oncogene encoded proteins is crucial to the pathogenesis of ovarian carcinoma and whether this provides any useful prognostic information. METHODS--The expression of the insulin-like growth factor 1 receptor (ILGFR 1), epidermal growth factor receptor (EGFR), and the c-erbB-2, c-ras, and c-myc products was studied by multiparameter flow cytometry in 80 patients with epithelial ovarian cancer for whom long term follow up was available. RESULTS--Overexpression of ILGFR 1, EGFR, c-erbB-2, c-ras and c-myc was found in, respectively, nine of 80 (11%), 10 of 80 (12%), 19 of 80 (24%), 16 of 80 (20%) and 28 of 80 (35%) ovarian carcinomas. The levels of expression of ILGFR 1, EGFR, c-erbB-2 and c-ras were significantly higher in the tumours of patients with recurrent or persistent disease after chemotherapy than in the tumours of patients at initial presentation (p < 0.02). Multivariate analysis showed that residual tumour (p < 0.001), FIGO stage (p = 0.002), EGFR overexpression (p = 0.030) and previous chemotherapy (p = 0.034) were independent variables for predicting survival. CONCLUSIONS--Overexpression of these oncoproteins only occurs in a small proportion of ovarian carcinomas but may have an important role in the progression of the disease.

https://jcp.bmj.com/content/jclinpath/47/10/914.full.pdf

Oncogenes and tumor progression.

Expression of c-erbB-2, c-myc, and c-ras oncoproteins, insulin-like growth factor receptor I, and epidermal growth factor receptor in ovarian carcinoma.

Current research indicates a role for several oncogenes in radiation-induced carcinogenesis in vivo and cell transformation in vitro. Certain oncogenes are probably also involved in some cases of human cancer caused by exposure to nonionizing radiation and may play a mechanistic role in the phenomenon of radioresistance seen in later stages of tumor progression. The mechanisms of oncogene activation seen in radiation-induced tumors include point mutations, gene amplification, and changes in gene expression. Genetic factors associated with target species, strain, and tissue type play an important role in determining the specific nature of oncogene activation by radiation exposure. Using the rat skin as a model for cancer induction by ionizing radiation, we found concurrent activation of K-ras and c-myc oncogenes in end-stage tumors. Amplification of the myc gene proved to occur during a late stage of tumor progression and is not an early initiating event resulting from the direct action of radiation on target cells. The importance of tissue specificity, tumor cell heterogeneity, and physical characteristics of the radiation exposure are discussed.

Oncogenes and Radiation Carcinogenesis

Several cellular processes such as cell cycle progression, apoptosis, cell adhesion and motility, cell growth, angiogenesis and differentiation are regulated by the MYC (here MYCN and c-MYC) proto-oncogenes. Elevated expression of MYC is present in a wide range of human tumors including Burkitt s Lymphoma, neuroblastoma, medulloblastoma, colon cancer and glioblastoma. In cancer, high MYC expression levels have been correlated with fast tumor growth and poor prognosis. Neuroblastoma, a heterogeneous childhood cancer has a broad clinical spectrum ranging from spontaneously regressing tumors to those with fast progression and an unfavorable outcome. One of the markers for poor survival is MYCN-amplification. Importantly, down-regulation of MYCN results in differentiation. While better treatment options has increased the overall survival for low-risk tumors, the survival of children with high-risk tumors has not improved and new therapeutic strategies such as targeting MYC are needed. Currently, there are no drugs directly targeting MYC available in the clinic. In paper I we demonstrated that several known c-MYC inhibitors also bind directly to MYCN and prevented MYCN/MAX interaction. We found that the affinities of the molecules correlated with growth inhibition of neuroblastoma cells. We further showed that the compounds lead to increased apoptosis in MYCN-amplified cells compared to non-amplified cells. In addition, treatment resulted in differentiation and lipid accumulation processes previously correlated to down-regulation of MYCN. These data show the proof-of-principle of directly targeting MYC. However, there is a great need for more potent and specific molecules targeting MYC. In paper II we have screened for new molecules targeting both MYCN and c-MYC. Using a cellbased assay we identified six compounds that target both MYC proteins. The small molecule #2.7 was chosen for further characterization due to its ability to directly targeting MYC. Treatment of MYCN-amplified and MYCN-non-amplified neuroblastoma cells with compound #2.7 lead to decreased proliferation in a MYCNdependent manner and to the inhibition of transformation by RAS and MYCN in vitro. Collectively, our results in paper I and II support the idea that direct targeting of MYC is a new strategy for cancer treatment. In paper III we demonstrated that MYCN upregulates the miR-17~92 cluster in neuroblastoma. Importantly, we showed that two members of the cluster miR-18a and miR-19a bind to and down-regulate the ESR1 gene encoding for the estrogen receptor-α (ER-α) thereby inhibiting differentiation of neuroblastoma cells. In contrast, ERoverexpression lead to neural differentiation. We further demonstrated ESR1 expression during normal development of the human sympathetic nervous system and showed a correlation between low ESR1 levels and poor survival. Based on these results, we suggest that targeting MYCN regulated miRNAs could be another strategy to treat MYCN-amplified neuroblastoma. The transactivation domain (TAD) of c-MYC is a highly flexible region, which is necessary for all of MYC’s functions. In order to gain more information about the c-MYC-TAD we have performed structural studies in paper IV. Circular Dichroism confirmed the presence of little secondary structure (about 9% α-helical and 30% β-sheet) in the mainly disordered (61%) c-MYC-TAD. Small-angle light scattering analysis suggested that the overall structure is most probably that of an elliptical cylinder. Our results show that small-angle light scattering together with NMR and CD might be used in future studies to gain even more insight in the structure of the c-MYC-TAD. Taken together, two approaches to target MYCN-amplified neuroblastoma can be suggested based on the data presented in this thesis. The MYCN protein could either be targeted directly with small molecules or indirectly by using anti-miRNAs. We have identified several novel small molecules that target MYC that will be characterized and may have potential for further development. Importantly, we have also aimed to increase the knowledge concerning the structure of the c-MYC transactivation domain. This new information may contribute to the development of future tailored and selective targeting of MYC and its interaction partners and may also give further insight to MYC function. LIST OF SCIENTIFIC PAPERS I. Inga Muller, Karin Larsson, Anna Frenzel, Ganna Oliynyk, Hanna Zirath, Edward V. Prochownik, Nicholas J. Westwood and Marie Arsenian Henriksson. Targeting of the MYCN protein with small molecule c-MYC inhibitors. PLoS One. 2014;9(5):e97285 II. Karin Ridderstrale*, Qinzi Yan*, Alina Castell, Per Hydbring, Inga Muller, Siti Mariam Zakaria, Camilla Mannich Uggla, Marie Arsenian Henriksson and LarsGunnar Larsson. Identification of low molecular weight compounds that target the MYC:MAX protein interaction and inhibit MYC-dependent tumor cell growth. Manuscript, 2014. *Equal contribution III. Jakob Loven, Nikolay Zinin, Therese Wahlstrom, Inga Muller, Petter Brodin, Erik Fredlund, Ulf Ribacke, Andor Pivarcsi, Sven Pahlman and Marie Henriksson. MYCN-regulated microRNAs repress estrogen receptor-α (ESR1) expression and neuronal differentiation in human neuroblastoma. Proceeding of the National Academy of Science (PNAS), 2010,107(4):1553-1558. IV. Inga Muller, Ranjana Sarma, Arnaud Chene, Eva Allerbring, Hannes Uchtenhagen, Elisabeth Kremmer, Bernhard Luscher, Per-Ake Nygren, Tatyana Sandalova, Marie Arsenian Henriksson* and Adnane Achour*. Structural analysis of the c-MYC transactivation domain reveals highly flexible regions in an extended rod like structure. Manuscript, 2014. *Equal contribution

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Bringing order to disorder : structural and functional analysis for development of strategies to target myc

Oncogenes, or tumor genes, are altered versions of normal cellular genes, generically known as protooncogenes, with potential properties for the induction of neoplastic transformation in either natural or experimental conditions (1,2). The term \"oncogene\" was coined by Hubner and Todaro to denote genes in endogenous retrovirus genomes that may playa role in oncogenesis (3). Oncogenes have been isolated from acute transforming retroviruses of avian, rodent, feline and primate origin but they are genes of eukaryotic cellular origin, not of viral origin (4,5). Retroviruses act only as transducers and the presence of oncogenes in their genome is generally attributed to recombinational events between retroviruses and eukaryotic cells (6). Cellular oncogenes are referred to as c-one genes, and their viral counterparts as v-onc genes (7,8). Each oncogene is usually represented by a three letter symbol related to the name of the retrovirus or the cell from which it was originally defined.

Oncogenes and tumor progression.

Citations

Expression of c-erbB-2, c-myc, and c-ras oncoproteins, insulin-like growth factor receptor I, and epidermal growth factor receptor in ovarian carcinoma.

Oncogenes and Radiation Carcinogenesis

Bringing order to disorder : structural and functional analysis for development of strategies to target myc

Retroviruses and cellular oncogenes

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