Aberrant promoter DNA methylation inhibits bone morphogenetic protein 2 expression and contributes to drug resistance in breast cancer

Du, Min; Su, Xiaomei; Zhang, Tao; Xing, Yong-Jun

doi:10.3892/mmr.2014.2276

Cited by 15 publications

(12 citation statements)

References 27 publications

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“…Bone morphogenic proteins are crucial for the development of both the central and peripheral nervous systems in vertebrates, regulating neural stem cell fate and maturation [ 30 , 31 ]. Their roles and regulation in chemo brain and tumor brain need to be further elucidated, especially given the fact that many of the BMP genes are epigenetically regulated via DNA methylation [ 32 ]. Our initial analysis suggested that non-CNS tumor growth led to demethylation of BMP4 promoter in the PFC tissues of tumor-bearing animals as compared to intact ones ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Chemo brain or tumor brain - that is the question: the presence of extracranial tumors profoundly affects molecular processes in the prefrontal cortex of TumorGraft mice

Kovalchuk

Ilnytskyy

Rodriguez-Juarez

et al. 2017

Aging

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Cancer chemotherapy causes numerous persistent central nervous system complications. This condition is known as chemo brain. Cognitive impairments occur even before treatment, and hence are referred to as cancer associated cognitive changes, or tumor brain. There is much yet to be learned about the mechanisms of both chemo brain and tumor brain. The frequency and timing of chemo brain and tumor brain occurrence and persistence strongly suggest they may be epigenetic in nature and associated with altered gene expression. Here we used TumorGraftTM models wherein part of a patient's tumor is removed and grafted into immune-deficient mice and conducted global gene expression and DNA methylation analysis. We show that malignant non-central nervous system tumor growth causes profound molecular alterations in the brain. Mice harbouring triple negative or progesterone positive breast cancer TumorGrafts exhibited altered gene expression, decreased levels of DNA methylation, increased levels of DNA hydroxymethylation, and oxidative stress in the prefrontal cortex. Interestingly, chemotherapy did not have any additional synergistic effects on the analyzed processes. The molecular changes observed in this study are known signs of neurodegeneration and brain aging. This study provides an important roadmap for future large-scale analysis of the molecular and cellular mechanisms of tumor brain.

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Section: Discussionmentioning

confidence: 99%

Chemo brain or tumor brain - that is the question: the presence of extracranial tumors profoundly affects molecular processes in the prefrontal cortex of TumorGraft mice

Kovalchuk

Ilnytskyy

Rodriguez-Juarez

et al. 2017

Aging

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“…The bottom gene in the list encodes Bone Morphogenetic Protein 2 (BMP2). Promoter DNA methylation of BMP2 contributes to drug resistance in breast cancer [ 20 ]. Another most commonly inactivated gene in various cancers, Ras association domain-containing protein 1, RASSF1 , undergoes either DNA methylation or chromosomal deletion in breast cancer [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation and hormone receptor status in breast cancer

et al. 2016

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BackgroundWe examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chicago (BCCC) study and using data from The Cancer Genome Atlas (TCGA).ResultsDNA was extracted from formalin-fixed, paraffin-embedded samples on 75 patients (21 White, 31 African-American, and 23 Hispanic) (training dataset) enrolled in the BCCC. Hormone receptor status was defined as negative if tumors were negative for both estrogen and progesterone (ER/PR) receptors (N = 22/75). DNA methylation was analyzed at 1505 CpG sites within 807 gene promoters using the Illumina GoldenGate assay. Differential DNA methylation as a predictor of hormone receptor status was tested while controlling for false discovery rate and assigned to the gene closest to the respective CpG site. Next, those genes that predicted ER/PR status were validated using TCGA data with respect to DNA methylation (validation dataset), and correlations between CpG methylation and gene expression were examined. In the training dataset, 5.7 % of promoter mean methylation values (46/807) were associated with receptor status at P < 0.05; for 88 % of these (38/46), hypermethylation was associated with receptor-positive disease. Hypermethylation for FZD9, MME, BCAP31, HDAC9, PAX6, SCGB3A1, PDGFRA, IGFBP3, and PTGS2 genes most strongly predicted receptor-positive disease. Twenty-one of 24 predictor genes from the training dataset were confirmed in the validation dataset. The level of DNA methylation at 19 out 22 genes, for which gene expression data were available, was associated with gene activity.ConclusionsHigher levels of promoter methylation strongly correlate with hormone receptor positive status of breast tumors. For most of the genes identified in our training dataset as ER/PR receptor status predictors, DNA methylation correlated with stable gene expression level. The predictors performed well when evaluated on independent set of samples, with different racioethnic distribution, thus providing evidence that this set of DNA methylation biomarkers will likely generalize to prospective patient samples.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0184-7) contains supplementary material, which is available to authorized users.

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“…Du et al. 64 reported that knockdown of BMP2 increased chemoresistance of the MCF-7 breast cancer cell line. Similarly, Liu et al.…”

Section: Main Textmentioning

confidence: 99%

The Dual Role of Bone Morphogenetic Proteins in Cancer

Bach

Park

Lee

2018

Molecular Therapy - Oncolytics

167

146

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Bone morphogenetic proteins (BMPs) are a diverse class of molecules with over 20 growth factor proteins that belong to the transforming growth factor-β (TGF-β) family and are highly associated with bone formation and disease development. Aberrant expression of various BMPs has been reported in several cancer tissues. Biological function studies have elicited the dual role of BMPs in both cancer development and suppression. Furthermore, a variety of BMP antagonists, ligands, and receptors have been shown to reduce or enhance tumorigenesis and metastasis. Knockout mouse models of BMP signaling components have also revealed that the suppression of BMP signaling impairs cancer metastasis. Herein, we highlight the basic clinical background and involvement of BMPs in modulating cancer progression and their dynamic interactions (e.g., with microRNAs) in the tumor microenvironment in addition to their mutations and roles in chemoprevention. We also suggest that BMPs should be considered a powerful putative therapeutic target in tumorigenesis and bone metastasis.

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Aberrant promoter DNA methylation inhibits bone morphogenetic protein 2 expression and contributes to drug resistance in breast cancer

Cited by 15 publications

References 27 publications

Chemo brain or tumor brain - that is the question: the presence of extracranial tumors profoundly affects molecular processes in the prefrontal cortex of TumorGraft mice

Chemo brain or tumor brain - that is the question: the presence of extracranial tumors profoundly affects molecular processes in the prefrontal cortex of TumorGraft mice

DNA methylation and hormone receptor status in breast cancer

The Dual Role of Bone Morphogenetic Proteins in Cancer

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