Transcriptome profiling identified differentially expressed genes and pathways associated with tamoxifen resistance in human breast cancer

Men, Xin; Jun, Ma; Wu, Tong; Pu, Junyi; Wen, Shaojia; Shen, Jianfeng; Wang, Xun; Wang, Yamin; Chen, Chao; Dai, Peng

doi:10.18632/oncotarget.23694

Cited by 25 publications

(23 citation statements)

References 35 publications

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“…Although CpG sites were not identical in all studies, DNAm changes at other loci in PTPRN2 and ABLIM2 were observed in two [(45) and the present study]. Recently, PTPRN2 has been identified as a possible obesity susceptibility gene (46), and its tumor expression was reported as a novel candidate biomarker and therapeutic target in estrogen receptor-positive breast cancer (47). Concerning the ABLIM2 gene, little is known besides its potential role in lung cancer metastasis (48) and regulation by estradiol (49).…”

Section: Discussionmentioning

confidence: 42%

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Association Between BMI and DNA Methylation in Blood or Normal Adult Breast Tissue: A Systematic Review

et al. 2020

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Background/Aim: Several studies have investigated the influence of obesity on DNA methylation (DNAm) to find biomarkers associated with the detection of chronic diseases, including breast cancer. The aim of the study was to systematically review studies examining the association of body mass index (BMI) and DNAm in blood or normal breast tissue. Materials and Methods: Three scientific literature databases (PubMed, Embase and Web of Science) were screened until May 2018. Results: Twenty-four studies were included along with ours in which we investigated this relation in the normal breast tissue of 40 breast cancer patients. Conclusion: BMIassociated CpG sites were highly variable with few identified in less than half of the studies. Nevertheless, a few genes potentially associated with BMI were highlighted in blood (CPT1A, ABCG1, SREBF1 and LGALS3BP) and in normal breast tissue (PTPRN2 and ABLIM2). The variability of the results could be explained by the tissue and cell-specificity of methylation and differences in methodology.

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Section: Discussionmentioning

confidence: 42%

“…In the literature, DNAm of PTPRN2 and HOXA3 gene expression have both been associated with obesity (71,72). Furthermore, DNAm of PTPRN2, HOXA3, C1orf70 and expression of PTPRN2, ABLIM2, NCKAP5 and LY6D have been linked to various cancers (48,(73)(74)(75)(76)(77)(78) including breast cancer (47,79).…”

Section: Discussionmentioning

confidence: 99%

Association Between BMI and DNA Methylation in Blood or Normal Adult Breast Tissue: A Systematic Review

et al. 2020

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“…These analyses showed that the most DEGs were enriched in binding category (more than 40% of 5,660 genes) [55]. Similarly, Men et al showed that a high proportion of DEGs found between tamoxifen-sensitive and tamoxifen-resistant MCF-7 breast cancer cell line belonged to the binding subcategories (2,836 genes, representing 93.35% of all DEGs) [56]. Moreover, Fang et al also found a high proportion of DEGs within the binding category (946 genes, representing 89.16% of all DEGs) when CDDP-resistant lung adenocarcinoma cell line A549 was compared to its parental A549 cell line [54].…”

Section: Discussionmentioning

confidence: 89%

Functional and transcriptomic characterization of cisplatin-resistant AGS and MKN-28 gastric cancer cell lines

et al. 2020

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Gastric cancer (GC) is a significant cancer-related cause of death worldwide. The most used chemotherapeutic regimen in GC is based on platinum drugs such as cisplatin (CDDP). However, CDDP resistance reduces advanced GC survival. In vitro drug-resistant cell model would help in the understanding of molecular mechanisms underlying this drugresistance phenomenon. The aim of this study was to characterize new models of CDDPresistant GC cell lines (AGS R-CDDP and MKN-28 R-CDDP) obtained through a stepwise increasing drug doses method, in order to understand the molecular mechanisms underlying chemoresistance as well as identify new therapeutic targets for the treatment of GC. Cell viability assays, cell death assays and the expression of resistance molecular markers confirmed that AGS R-CDDP and MKN-28 R-CDDP are reliable CDDP-resistant models. RNAseq and bioinformatics analyses identified a total of 189 DEGs, including 178 up-regulated genes and 11 down-regulated genes, associated mainly to molecular functions involved in CDDP-resistance. DEGs were enriched in 23 metabolic pathways, among which the most enriched was the inflammation mediated by chemokine and cytokine signaling pathway. Finally, the higher mRNA expression of SERPINA1, BTC and CCL5, three up-regulated DEGs associated to CDDP resistance found by RNA-seq analysis was confirmed. In summary, this study showed that AGS R-CDDP and MKN-28 R-CDDP are reliable models of CDDP resistance because resemble many of resistant phenotype in GC, being also useful to assess potential therapeutic targets for the treatment of gastric cancers resistant to CDDP. In addition, we identified several DEGs associated with molecular functions such as binding, catalytic activity, transcription regulator activity and transporter activity, as well as signaling pathways associated with inflammation process, which could be involved in the development of CDDP resistance in GC. Further studies are necessary to clarify the role of

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“…[ 31 ] (which uses random forest approach as a base), and mRNA data alone (without considering molecular pathways) and demonstrated that our method outperforms these techniques in predicting risk of resistance to tamoxifen. Furthermore, we have compared our pathway signature to other known signatures of tamoxifen response [18] , [19] , [20] and have shown the superiority of our pathway-based approach (adjusted hazard ratio = 3.11, hazard p-value = 0.0278). Finally, to enhance clinical applicability of our finding, we derived five read-out genes (each of which reflects activity changes in a corresponding pathway) and defined their treatment failure scoring system, indicating risk of developing tamoxifen resistance in two patient cohorts (Test cohort 1, adjusted hazard ratio = 3.1; Test cohort 2, adjusted hazard ratio = 6.95).…”

Section: Introductionmentioning

confidence: 96%

“…In recent years, several groups have developed gene expression signatures of tamoxifen response for ER+ patients, including 10 gene-signature by Men et al. [ 18 ], 21 gene-signature by Paik et al. [ 19 ] (known as Oncotype DX), and 2 gene-signature by Ma et al.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis of therapeutic response uncovers molecular pathways governing tamoxifen resistance in ER+ breast cancer

et al. 2020

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Background Prioritization of breast cancer patients based on the risk of resistance to tamoxifen plays a significant role in personalized therapeutic planning and improving disease course and outcomes. Methods In this work, we demonstrate that a genome-wide pathway-centric computational framework elucidates molecular pathways as markers of tamoxifen resistance in ER+ breast cancer patients. In particular, we associated activity levels of molecular pathways with a wide spectrum of response to tamoxifen, which defined markers of tamoxifen resistance in patients with ER+ breast cancer. Findings We identified five biological pathways as markers of tamoxifen failure and demonstrated their ability to predict the risk of tamoxifen resistance in two independent patient cohorts (Test cohort1: log-rank p-value = 0.02, adjusted HR = 3.11; Test cohort2: log-rank p-value = 0.01, adjusted HR = 4.24). We have shown that these pathways are not markers of aggressiveness and outperform known markers of tamoxifen response. Furthermore, for adoption into clinic, we derived a list of pathway read-out genes and their associated scoring system, which assigns a risk of tamoxifen resistance for new incoming patients. Interpretation We propose that the identified pathways and their read-out genes can be utilized to prioritize patients who would benefit from tamoxifen treatment and patients at risk of tamoxifen resistance that should be offered alternative regimens. Funding This work was supported by the Rutgers SHP Dean's research grant, Rutgers start-up funds, Libyan Ministry of Higher Education and Scientific Research, and Katrina Kehlet Graduate Award from The NJ Chapter of the Healthcare Information Management Systems Society.

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Transcriptome profiling identified differentially expressed genes and pathways associated with tamoxifen resistance in human breast cancer

Cited by 25 publications

References 35 publications

Association Between BMI and DNA Methylation in Blood or Normal Adult Breast Tissue: A Systematic Review

Association Between BMI and DNA Methylation in Blood or Normal Adult Breast Tissue: A Systematic Review

Functional and transcriptomic characterization of cisplatin-resistant AGS and MKN-28 gastric cancer cell lines

Genome-wide analysis of therapeutic response uncovers molecular pathways governing tamoxifen resistance in ER+ breast cancer

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