Activation of KRAS promotes the mesenchymal features of basal-type breast cancer

Kim, Rae Kwon; Suh, Yongjoon; Yoo, Kyoungkeun; Cui, Yan Hong; Kim, Hyeonmi; Kim, Min Jung; Kim, In Gyu; Lee, Su Jae

doi:10.1038/emm.2014.99

Cited by 67 publications

(53 citation statements)

References 25 publications

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“…The KRAS gene, located in 12p12.1, encodes a protein that is a member of the small gTPase superfamily (48). Recently, an abnormal KRAS expression has been reported to be involved in human cancers, such as gastric (27), pancreatic (28), bladder (29), lung (49) and breast cancer (50). In adittion, aberrantly expressed and somatic activating mutations in KRAS are involved in tumourigenesis and tumour development, including pilocytic astrocytoma (51), nasopharyngeal carcinoma (52), colorectal (53) and lung cancer (54).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways

Kang

Zhang

et al. 2017

Oncol Rep

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Abstract. Melanoma is the seventh most common malignancy in females and the fifth most common cancer in males worldwide. An increasing number of studies have reported that microRNA (miRNA) dysregulation is frequently observed in various types of human cancers, including melanoma. Abnormally expressed miRNAs play an important role in melanoma formation and progression by serving as potential biomarkers and therapeutic targets. Recently, miRNA-326 (miR-326) has been reported to be differentially expressed in various types of tissues and play important roles in tumourigenesis and tumour development. However, the expression levels, biological roles and underlying mechanisms of miR-326 in melanoma remain unknown. In the present study, we demonstrated that miR-326 was significantly downregulated in melanoma tissues and cell lines. Functional assays revealed that the enforced expression of miR-326 suppressed melanoma cell proliferation and invasion and increased cell apoptosis in vitro. Using bioinformatic analysis, Kirsten rat sarcoma viral oncogene homolog (KRAS) was predicted as a potential target of miR-326. Luciferase reporter assay confirmed that miR-326 could directly target the 3'-untranslated region of KRAS. In addition, reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that miR-326 upregulation decreased the KRAS expression in melanoma cells at both the mRNA and protein level. Furthermore, KRAS was upregulated in melanoma tissues and inversely correlated with miR-326 expression. In addition, the KRAS knockdown phenocopied the tumour-suppressing effects of miR-326 overexpression on melanoma cells. The restoration of the expression of KRAS markedly reversed the antitumour effects induced by miR-326 overexpression in melanoma cells. Further experiments indicated that miR-326 inactivated the AKT and ERK signalling pathways in melanoma. Collectively, these results revealed that miR-326 serves as a tumour suppressor in melanoma by targeting KRAS and regulating the AKT and ERK signalling pathways, indicating that miR-326 may be a promising therapeutic target for melanoma patients.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways

Kang

Zhang

et al. 2017

Oncol Rep

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“…This gene mainly functions in signaling pathways involving membrane receptors and cAMP. KRAS has the strongest influence on malignant cancer in the RAS family (9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

miR‑202 acts as a potential tumor suppressor in breast cancer

et al. 2018

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Abstract. Breast cancer affects ~10% of women worldwide and is responsible for ~12% of all cancer-associated mortalities. Breast cancer is more prone to metastasis compared with other types of cancer. Up to 5% of patients with breast cancer present with incurable metastasis and an additional 10-15% of patients develop metastases within 3 years of their initial diagnosis. MicroRNAs (miRNAs) are short RNAs, 21-25 nucleotides in length, that have been shown to significantly affect gene expression. In total >2,000 miRNAs have been identified and specific miRNAs have been revealed to be associated with cancer. In the present study, we observed that the majority of breast cancer specimens collected expressed low levels of miR-202 compared with adjacent tissues and normal cell lines. Mechanistic investigations identified KRAS as a potential target gene of miR-202 and it was demonstrated that miR-202 exerted its tumor-suppressive effects by regulating the expression of KRAS in breast cancer cells. Functional assays revealed that miR-202 significantly reduced cell proliferation, migration and invasion in vitro. In summary, these results indicate the function of miR-202 in breast cancer progression and suggest that its use within breast cancer therapy is promising. IntroductionBreast cancer is one of the most common malignant tumors in women. In many areas, breast cancer is the most common malignancy in females. In China, the incidence of breast cancer is increasing annually. Because the development and progression of breast cancer are complex processes involving many genes, the underlying mechanism of breast cancer remains unclear (1,2).Single-stranded RNAs consisting of 19 to 25 nucleotides are known as microRNAs (miRNAs). These RNAs are regulatory molecules that modulate the expression of functional genes, play an important role in many biological processes, and are expressed in a tissue-and time-specific manner. miRNAs regulate gene expression at the post-transcriptional level mainly via completely complementary or partially complementary binding to the 3' UTR of the target gene, resulting in degradation or translational repression of the target gene (2-4). Studies have shown that a variety of miRNAs are involved in malignant transformation processes, such as malignant proliferation, metastasis and recurrence, and apoptosis inhibition. Studies have reported that miRNA inhibitors can reduce the high miR-21 expression in breast cancer cells, inhibiting proliferation and migration; that miR-373 can promote the metastasis of breast cancer cells; that miR-520 plays a role in promoting the development of breast cancer; and that miR-126 and miR-335 are able to inhibit breast cancer to a certain extent (5-7). Recent studies have demonstrated that miR-202 is associated with several types of cancer, miR-202 has a lower expression in several of cancers, and however, the expression and function of miR-202 have not been investigated in breast cancer (8).KRAS belongs to the RAS family; it is located on the short arm of chromosome 1...

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“…Several significant pathways were found to be occurring more frequently in Basal-specific SCNAs, including HALLMARK_SPERMATOGENESIS, HALLMARK_KRAS_SIGNALING_UP, HALLMARK_E2F_TARGETS, HALLMARK_BILE_ACID_METABOLISM, HALLMARK_FATTY_ACID_METABOLISM, HALLMARK_UV_RESPONSE_UP, HALLMARK_MYOGENESIS (FDR < 0.05). The enrichment of KRAS signaling can be explained by published evidence supporting KRAS activation in basal-type breast cancer cells compared to luminal cells (Kim et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

iEDGE: integration of Epi-DNA and Gene Expression and applications to the discovery of somatic copy number-associated drivers in cancer

Chapuy

Varelas

et al. 2019

Preprint

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22The emergence of large-scale multi-omics data warrants method development for data integration. 23Genomic studies from cancer patients have identified epigenetic and genetic regulatorssuch as 24 methylation marks, somatic mutations, and somatic copy number alterations (SCNAs), among othersas 25 predictive features of cancer outcome. However, identification of "driver genes" associated with a given 26 alteration remains a challenge. To this end, we developed a computational tool, iEDGE, to model cis and 27 trans effects of (epi-)DNA alterations and identify potential cis driver genes, where cis and trans genes 28 denote those genes falling within and outside the genomic boundaries of a given (epi-)genetic alteration, 29 respectively. 30First, iEDGE identifies the cis and trans genes associated with the presence/absence of a particular epi-31 DNA alteration across samples. Tests of statistical mediation are then performed to determine the cis 32 genes predictive of the trans gene expression. Finally, cis and trans effects are annotated by pathway 33 enrichment analysis to gain insights into the underlying regulatory networks. 34We used iEDGE to perform integrative analysis of SCNAs and gene expression data from breast cancer 35 and 18 additional cancer types included in The Cancer Genome Atlas (TCGA). Notably, cis gene drivers 36 identified by iEDGE were found to be significantly enriched for known driver genes from multiple 37 compendia of validated oncogenes and tumor suppressors, suggesting that the remainder are of equal 38 importance. Furthermore, predicted drivers were enriched for functionally relevant cancer genes with 39 amplification-driven dependencies, which are of potential prognostic and therapeutic value. All the 40 analyses results are accessible at https://montilab.bu.edu/iEDGE. 41 55 development. Furthermore, the generated analysis results are often static, and not accessible in an 56 interactive fashion. The approach presented here aims to address both of these shortcomings. 57The central hypothesis behind integrative approaches is that the integration of multi-level genomics data 58 allows for prioritization of putative cancer "drivers" that are potential biomarkers or therapeutic targets. 59An important genetic alteration type in cancer is somatic copy-number alterations (SCNAs). SCNAs 60 harbor many known cancer drivers (oncogenes or tumor suppressors) and play an important role in cancer 61 initiation and/or progression through activation of oncogenes and inactivation of tumor suppressors 62 (Beroukhim et al. 2010; Zack et al. 2013). Identification of unknown SCNA-associated cancer drivers is 63 complicated by the fact that each SCNA contains many genes, often even a complete chromosome arm, 64 the majority of which is likely not to confer any selective advantage (i.e., passengers). One approach to 111 SCNAs. For instance, gene sets HALLMARK_ESTROGEN_RESPONSE_LATE, 112 HALLMARK_ESTROGEN_RESPONSE_EARLY, HALLMARK_G2M_CHECKPOINT were 113 significant hits in more than 75% of SCNAs. These gene s...

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Activation of KRAS promotes the mesenchymal features of basal-type breast cancer

Cited by 67 publications

References 25 publications

MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways

MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways

miR‑202 acts as a potential tumor suppressor in breast cancer

iEDGE: integration of Epi-DNA and Gene Expression and applications to the discovery of somatic copy number-associated drivers in cancer

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