Mutational Activation of K-Ras Oncogene in Human Breast-Tumors

Koffa, Maria; Malamoumitsi,; Agnantis, N.J.; Spandidos, Demetrios Α.

doi:10.3892/ijo.4.3.573

Cited by 13 publications

(10 citation statements)

References 10 publications

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“…The MDA-MB-231 cells are often used as a model of aggressive breast cancer cells. Intriguingly they also harbor a Ras mutation (KRAS G13D ) (50) similar to the NRAS Q61N in SK-Mel-147. Additional work is needed to assess the generality of these observations.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma

Haak

Appleton

Lisabeth

et al. 2017

Molecular Cancer Therapeutics

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Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Evidence implicates Rho-activated gene transcription in melanoma metastasis mediated by the nuclear localization of the transcriptional coactivator, myocardin-related transcription factor (MRTF). Here, we highlight a role for Rho and MRTF signaling and its reversal by pharmacologic inhibition using in vitro and in vivo models of human melanoma growth and metastasis. Using two cellular models of melanoma, we clearly show that one cell type, SK-Mel-147, is highly metastatic, has high RhoC expression, and MRTF nuclear localization and activity. Conversely, SK-Mel-19 melanoma cells have low RhoC expression, and decreased levels of MRTF-regulated genes. To probe the dependence of melanoma aggressiveness to MRTF transcription, we use a previously developed small molecule inhibitor, CCG-203971, which at low micro-molar concentrations blocks nuclear localization and activity of MRTF-A. In SK-Mel-147 cells, CCG-203971 inhibits cellular migration and invasion, and decreases MRTF target gene expression. In addition, CCG-203971-mediated inhibition of the Rho/MRTF pathway significantly reduces cell growth and clonogenicity and causes G1 cell cycle arrest. In an experimental model of melanoma lung metastasis, the RhoC-overexpressing melanoma cells (SK-Mel-147) exhibited pronounced lung colonization compared to the low RhoC expressing SK-Mel-19. Furthermore, pharmacological inhibition of the MRTF pathway reduced both the number and size of lung metastasis resulting in a marked reduction of total lung tumor burden. These data link Rho and MRTF-mediated signaling with aggressive phenotypes and support targeting the MRTF transcriptional pathway as a novel approach to melanoma therapeutics.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma

Haak

Appleton

Lisabeth

et al. 2017

Molecular Cancer Therapeutics

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“…In breast cancer development, up-regulation of the KRAS/MAPK signaling can occur through multiple facets, and it has been shown to be increased in many breast cancer samples either by over-expression of growth-factor-receptor tyrosine kinases primarily HER2/ErbB-2, EGFR, and IGFR or by activating mutations [22], [23], [24], [25]. Although KRAS is frequently mutated in human cancers including pancreatic, colorectal and lung cancers, KRAS mutations are extremely rare in breast cancer [26], [27]. However wild-type KRAS is significantly activated in breast cancers that over-express EGFR and ErbB2 [28].…”

Section: Discussionmentioning

confidence: 99%

Deregulated miRNAs in Hereditary Breast Cancer Revealed a Role for miR-30c in Regulating KRAS Oncogene

et al. 2012

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Aberrant miRNA expression has been previously established in breast cancer and has clinical relevance. However, no studies so far have defined miRNAs deregulated in hereditary breast tumors. In this study we investigated the role of miRNAs in hereditary breast tumors comparing with normal breast tissue. Global miRNA expression profiling using Exiqon microarrays was performed on 22 hereditary breast tumors and 15 non-tumoral breast tissues. We identified 19 miRNAs differentially expressed, most of them down-regulated in tumors. An important proportion of deregulated miRNAs in hereditary tumors were previously identified commonly deregulated in sporadic breast tumors. Under-expression of these miRNAs was validated by qRT-PCR in additional 18 sporadic breast tumors and their normal breast tissue counterparts. Pathway enrichment analysis revealed that deregulated miRNAs collectively targeted a number of genes belonging to signaling pathways such as MAPK, ErbB, mTOR, and those regulating cell motility or adhesion. In silico prediction detected KRAS oncogene as target of several deregulated miRNAs. In particular, we experimentally validated KRAS as a miR-30c target. Luciferase assays confirmed that miR-30c binds the 3′UTR of KRAS transcripts and expression of pre-miR-30c down-regulated KRAS mRNA and protein. Furthermore, miR-30c overexpression inhibited proliferation of breast cancer cells. Our results identify miRNAs associated to hereditary breast cancer, as well as miRNAs commonly miss-expressed in hereditary and sporadic tumors, suggesting common underlying mechanisms of tumor progression. In addition, we provide evidence that KRAS is a target of miR-30c, and that this miRNA suppresses breast cancer cell growth potentially through inhibition of KRAS signaling.

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“…[13][14][15] The PCR products were processed with the Wizard PCR Preps DNA purification Clean kit (Promega, Southampton, UK) to remove unincorporated primers and dNTP. In the case of Ki-ras and N-ras, 10 ml of the PCR product was digested overnight with 30 U of BstNI endonuclease (New England BioLabs Inc., USA) at 601C, in a buffer solution containing 50 mM NaCl, 10 mM TrisHCl, 10 mM MgCl 2 , 1 mM dithiothreitol, and 100 mg/ml BSA (pH ¼ 7.9).…”

Section: Methodsmentioning

confidence: 99%

Detection of point mutations at codon 12 of KI-ras in ophthalmic pterygia

Detorakis

Zafiropoulos

Arvanitis

et al. 2004

Eye

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Aims Ophthalmic pterygium is a potentially vision-threatening lesion of unknown etiology, related to an exposure to solar light. Mutations to the ras genes are frequently observed in lesions related to an exposure to solar light. The present study aims at screening pterygia for mutations at codons 12 and 13 of the ras genes. Methods In all, 50 pterygia were examined, together with respective blood samples and specimens of normal conjunctiva. A PCR reaction was performed to amplify sequences containing codons 12 and 13 of Ki-ras, H-ras, and N-ras. An RFLP analysis was then performed to detect point mutations at codon 12. The mutational status at codons 12 and 13 was further explored with sequencing of PCR products.Results RFLP analysis revealed Ki-ras mutations at codon 12 in five (10%) of pterygia, whereas H-ras or N-ras mutations were not observed. Sequencing confirmed Ki-ras mutations at codon 12 and revealed absence of mutations at codon 13. The presence of Ki-ras mutations was significantly correlated with postoperative recurrence (P ¼ 0.02) and young age (P ¼ 0.04). Mutations were not observed in specimens of blood or normal conjunctiva for any of the genes examined. Conclusions The absence of N-ras mutations is in agreement with previous reports concerning mucosal lesions. The detection of Ki-ras mutations and the association with postoperative recurrence implies a possible role of Ki-ras in the clinical profile of pterygium. The mechanism of Ki-ras mutations is unclear and could be independent of the action of UV light.

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Mutational Activation of K-Ras Oncogene in Human Breast-Tumors

Cited by 13 publications

References 10 publications

Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma

Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma

Deregulated miRNAs in Hereditary Breast Cancer Revealed a Role for miR-30c in Regulating KRAS Oncogene

Detection of point mutations at codon 12 of KI-ras in ophthalmic pterygia

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