Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1

Coyle, Krysta M.; Murphy, John P.; Vidovic, Dejan; Vaghar-Kashani, Ahmad; Dean, Cheryl A.; Sultan, Mohammad; Clements, Derek R.; Wallace, Melissa; Thomas, Margaret Lois; Hundert, Amos; Giacomantonio, Carman A.; Helyer, Lucy; Gujar, Shashi; Lee, Patrick W.K.; Weaver, Ian C.G.; Marcato, Paola

doi:10.18632/oncotarget.9858

Cited by 26 publications

(23 citation statements)

References 53 publications

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“…Consistent with our previous data [ 16 , 41 ], we confirmed that ALDH1A3 is the most predominant retinaldehyde dehydrogenase mRNA expressed in TNBC ( Figure 2 E), with the exceptions of HCC70 and SUM159. While the expression of retinaldehyde dehydrogenases may contribute to stem-like characteristics in breast cancer [ 42 , 43 , 44 ], we identify no correlation between atRA sensitivity and the expression of ALDH1A1, ALDH1A2, ALDH1A3, or ALDH8A1 ( Figure 2 E); or with differential expression of these isoforms following atRA treatment ( Figure 2 F).…”

Section: Resultssupporting

confidence: 93%

DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid

Coyle

Dean

Thomas

et al. 2018

Cancers

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All-trans retinoic acid (atRA) regulates gene expression and is used to treat acute promyelocytic leukemia. Attempts to use atRA in breast cancer without a stratification strategy have resulted in limited overall effectiveness. To identify biomarkers for the treatment of triple-negative breast cancer (TNBC) with atRA, we characterized the effects of atRA on the tumor growth of 13 TNBC cell lines. This resulted in a range of effects that was not predictable based on previously hypothesized predictors of response, such as the levels of atRA nuclear shuttling proteins fatty acid binding protein 5 (FABP5) and cellular retinoic acid binding protein 2 (CRABP2). Transcriptional profiling revealed that atRA induced distinct gene expression changes in the sensitive versus resistant cell lines that were mostly independent of the presence of retinoic acid response elements (RAREs) or peroxisome proliferator response elements (PPREs). Given the importance of DNA methylation in regulating gene expression, we hypothesized that differential DNA methylation could predict the response of TNBCs to atRA. We identified over 1400 sites that were differentially methylated between atRA resistant and sensitive cell lines. These CpG sites predicted the response of four TNBC patient-derived xenografts to atRA, and we utilized these xenografts to refine the profile and identified that as many as 17% of TNBC patients could benefit from atRA treatment. These data illustrate that differential methylation of specific CpGs may be useful biomarkers for predicting the response of patient tumors to atRA treatment.

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Section: Resultssupporting

confidence: 93%

DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid

Coyle

Dean

Thomas

et al. 2018

Cancers

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“…Although ALDH1A3 is characterized primarily as a retinaldehyde dehydrogenase, we identified limited overlap between the ALDH1A3-upregulated and the atRA-upregulated transcriptional profiles in both cell lines. While we and others have demonstrated a clear role for ALDH1A3 in initiating retinoid signaling and affecting the expression of RARE-containing genes including RARβ, the tumor suppressor gene RARRES1, and tissue transglutaminase 8 , 42 , 78 , the sole contribution of ALDH1A3 as a retinaldehyde dehydrogenase in breast cancer and the stem cell phenotype (cancerous or non-cancerous) may be overstated 8 , 41 , 44 , 79 – 81 . Alternate functions of ALDH1A3 may contribute to breast cancer progression and stem-cell activity.…”

Section: Discussionmentioning

confidence: 66%

Profiling of the transcriptional response to all-trans retinoic acid in breast cancer cells reveals RARE-independent mechanisms of gene expression

Coyle

Maxwell

Thomas

et al. 2017

Sci Rep

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Retinoids, derivatives of vitamin A, are key physiological molecules with regulatory effects on cell differentiation, proliferation and apoptosis. As a result, they are of interest for cancer therapy. Specifically, models of breast cancer have varied responses to manipulations of retinoid signaling. This study characterizes the transcriptional response of MDA-MB-231 and MDA-MB-468 breast cancer cells to retinaldehyde dehydrogenase 1A3 (ALDH1A3) and all-trans retinoic acid (atRA). We demonstrate limited overlap between ALDH1A3-induced gene expression and atRA-induced gene expression in both cell lines, suggesting that the function of ALDH1A3 in breast cancer progression extends beyond its role as a retinaldehyde dehydrogenase. Our data reveals divergent transcriptional responses to atRA, which are largely independent of genomic retinoic acid response elements (RAREs) and consistent with the opposing responses of MDA-MB-231 and MDA-MB-468 to in vivo atRA treatment. We identify transcription factors associated with each gene set. Manipulation of the IRF1 transcription factor demonstrates that it is the level of atRA-inducible and epigenetically regulated transcription factors that determine expression of target genes (e.g. CTSS, cathepsin S). This study provides a paradigm for complex responses of breast cancer models to atRA treatment, and illustrates the need to characterize RARE-independent responses to atRA in a variety of models.

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“…Functional analyses revealed that NRAD1 is nuclear localized with genome-wide chromatin interactions enriched among the genes it regulates. Finally, NRAD1 is a novel downstream target of aldehyde dehydrogenase 1A3 (ALDH1A3) and the first lncRNA described to contribute to gene expression changes induced by this CSC marker and mediator of tumor progression [23][24][25][26][27][28][29][30][31]. Together, these data identify the lncRNA NRAD1 as a novel oncogenic effector that is targetable with antisense oligonucleotides in the treatment of TNBC and reduction of cells with CSC characteristics.…”

Section: Introductionmentioning

confidence: 94%

ALDH1A3-regulated long non-coding RNA NRAD1 is a potential novel target for triple-negative breast tumors and cancer stem cells

et al. 2019

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To discover novel therapeutic targets for triple-negative breast cancer (TNBC) and cancer stem cells (CSCs), we screened long non-coding RNAs (lncRNAs) most enriched in TNBCs for high expression in CSCs defined by high Aldefluor activity and associated with worse patient outcomes. This led to the identification of non-coding RNA in the aldehyde dehydrogenase 1 A pathway (NRAD1), also known as LINC00284. Targeting NRAD1 in TNBC tumors using antisense oligonucleotides reduced cell survival, tumor growth, and the number of cells with CSC characteristics. Expression of NRAD1 is regulated by an enzyme that causes Aldefluor activity in CSCs, aldehyde dehydrogenase 1A3 (ALDH1A3) and its product retinoic acid. Cellular fractionation revealed that NRAD1 is primarily nuclear localized, which suggested a potential function in gene regulation. This was confirmed by transcriptome profiling and chromatin isolation by RNA purification, followed by sequencing (ChIRP-seq), which demonstrated that NRAD1 has enriched chromatin interactions among the genes it regulates. Gene Ontology enrichment analysis revealed that NRAD1 regulates expression of genes involved in differentiation and catabolic processes. NRAD1 also contributes to gene expression changes induced by ALDH1A3; thereby, the induction of NRAD1 is a novel mechanism through which ALDH1A3 regulates gene expression. Together, these data identify lncRNA NRAD1 as a downstream effector of ALDH1A3, and a target for TNBCs and CSCs, with functions in cell survival and regulation of gene expression.

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Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1

Cited by 26 publications

References 53 publications

DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid

DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid

Profiling of the transcriptional response to all-trans retinoic acid in breast cancer cells reveals RARE-independent mechanisms of gene expression

ALDH1A3-regulated long non-coding RNA NRAD1 is a potential novel target for triple-negative breast tumors and cancer stem cells

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