Expression Profiling after Induction of Demethylation in MCF-7 Breast Cancer Cells Identifies Involvement of TNF-α Mediated Cancer Pathways

Kim, Ju Hee; Kang, Seongeun; Kim, Tae Woo; Ye, Lihong; Liu, Ran; Kim, Sun Jung

doi:10.1007/s10059-012-2182-8

Cited by 10 publications

(7 citation statements)

References 35 publications

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“…S2b ). Furthermore, MCF7 cells treated with 5-azacytidine expressed higher levels of PTGER4 33 ( Supplementary Fig. 8 ), consistent with the hypothesis that DNA hypomethylation directly regulates expression.…”

Section: Resultssupporting

confidence: 85%

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Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

et al. 2016

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Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance—especially epigenetic events that alter gene expression—are however not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired aromatase inhibitor resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen independent growth. Our exploratory analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI resistant breast cancer treatment.

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Section: Resultssupporting

confidence: 85%

“…Interestingly, PTGER4 is unmethylated and expressed in normal breast tissue. MCF7 cells treated with demethylating agents increase PTGER4 mRNA levels, consistent with DNA methylation playing a direct role in its transcriptional regulation 33 ( Supplementary Fig. S8 ).…”

Section: Discussionsupporting

confidence: 64%

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

et al. 2016

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Section: Discussionmentioning

confidence: 55%

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

Hiken

McDonald

Decker

et al. 2016

Preprint

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Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance-especially epigenetic events that alter gene expression-are however not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired aromatase inhibitor resistance indicated that prostaglandin E 2 receptor 4 (PTGER4) is up-regulated after demethylation in resistant cells.Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen independent growth. Our exploratory analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI resistant breast cancer treatment.

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“…In detail, authors showed that coculture of MM cells with MM-BMSCs induced downregulation of the DNA-methyltransferase DNMT1 along with RANK-L promoter demethylation in MM cells. The authors hypothesized that, among the soluble factors secreted by BMSCs, TNF α could be responsible for the phenomena described above [ 75 ]. Indeed, treatment with TNF α increased miR-140-3p and miR-126 expression in MM cells, which are under the control of TNF α , and led to repression of DNMT1 transcription and RANK-L expression; conversely, the anti-TNF α antibody partially abrogated RANK-L expression [ 76 ].…”

Section: Mirna-based Regulation Of MM Cells By the Bmmmentioning

confidence: 99%

MicroRNAs: Novel Crossroads between Myeloma Cells and the Bone Marrow Microenvironment

Raimondi¹,

Luca²,

Morelli

et al. 2016

BioMed Research International

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Multiple myeloma (MM) is a hematologic malignancy of differentiated plasma cells that accumulate in the bone marrow, where a complex microenvironment made by different cell types supports proliferation, survival, and drug resistance of tumor cells. MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression at posttranscriptional level. Emerging evidence indicates that miRNAs are aberrantly expressed or functionally deregulated in MM cells as the result of multiple genetic or epigenetic mechanisms and that also the tumor microenvironment regulates MM cell functions by miRNAs. Consistently, modulation of miRNA levels in MM cells has been demonstrated to impair their functional interaction with the bone marrow microenvironment and to produce significant antitumor activity even able to overcome the protective bone marrow milieu. This review will describe the most recent findings on miRNA function in the context of MM bone marrow microenvironment, focusing on the therapeutic potential of miRNA-based approaches.

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Expression Profiling after Induction of Demethylation in MCF-7 Breast Cancer Cells Identifies Involvement of TNF-α Mediated Cancer Pathways

Cited by 10 publications

References 35 publications

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

MicroRNAs: Novel Crossroads between Myeloma Cells and the Bone Marrow Microenvironment

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