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Effect of Selective Androgen Receptor Modulator (SARM) on Gene Expression in Triple-Negative Breast Cancer Cells, MDA-MB-231-AR

ABSTRACT: RNA from tumors treated with vehicle or 30 mg/kg GTx-027 were pooled and subjected to microarray analysis. Genes that were increased or decreased by 2-fold or more were considered for further analyses. Unlike in prostate cancer, where AR agonists induce more genes than they repress, in MDA-MB-231-AR tumors, GTx-027 inhibited 2.5X the number of genes (1092 vs. 456) than it activated. Functional clustering of the genes indicated that GTx-027 modified more breast cancer genes than other pathway genes. Genes that regulate the function of others cancers, such as colorectal, lung, and oral, and metabolic diseases were also favorably altered by GTx-027. Breast cancer proliferative genes, such as aurora kinase, ERCC1, IGFBP3 were inhibited and growth inhibitory genes, such as NQO1, PTPRJ were activated by GTx-027. Many of the established androgen responsive-genes were also activated by GTx-027, indicating that breast cancer growth inhibitory role of GTx-027 evolved from its agonistic activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58196 | GEO | 2014/06/03

SECONDARY ACCESSION(S): PRJNA251550

REPOSITORIES: GEO

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Effect of Selective Androgen Receptor Modulator (SARM) on Gene Expression in Triple-Negative Breast Cancer Cells, MDA-MB-231-AR

Project description:RNA from tumors treated with vehicle or 30 mg/kg GTx-027 were pooled and subjected to microarray analysis. Genes that were increased or decreased by 2-fold or more were considered for further analyses. Unlike in prostate cancer, where AR agonists induce more genes than they repress, in MDA-MB-231-AR tumors, GTx-027 inhibited 2.5X the number of genes (1092 vs. 456) than it activated. Functional clustering of the genes indicated that GTx-027 modified more breast cancer genes than other pathway genes. Genes that regulate the function of others cancers, such as colorectal, lung, and oral, and metabolic diseases were also favorably altered by GTx-027. Breast cancer proliferative genes, such as aurora kinase, ERCC1, IGFBP3 were inhibited and growth inhibitory genes, such as NQO1, PTPRJ were activated by GTx-027. Many of the established androgen responsive-genes were also activated by GTx-027, indicating that breast cancer growth inhibitory role of GTx-027 evolved from its agonistic activity. A mixture of cells was suspended in 0.05 ml RPMI+10% FBS and 0.05 ml Matrigel/animal and was injected subcutaneously. Once the tumor size reached 200-300 mm3, the animals were randomized and treated orally with the indicated drugs formulated in Tween 80:Captex 200:water (0.8:0.2:9). Tumor volume and body weight were measured thrice weekly. At the end of study, animals were sacrificed, tumors excised, weighed, and stored for various analyses. RNA from tumors was isolated and verified qualitatively and quantitatively. Samples from each group (n=8; 100 ng/µl; total 1000 ng) were pooled and hybridized to Affymetrix human ST2.0 gene array. Data from the array were analyzed using Ingenuity Pathway Analysis software (IPA3).

2014-06-03 | E-GEOD-58196 | biostudies-arrayexpress

Overcoming Resistance to Anabolic SARM therapy in Experimental Cancer Cachexia with an HDAC Inhibitor

Project description:No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late stage clinical failures of anabolic anti-cachexia therapy, and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anti-cachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hind limb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated β-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.

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2024-01-30 | PXD047997 | Pride

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2016-07-18 | E-GEOD-70162 | biostudies-arrayexpress

Genome-wide analysis of PIAS1 on AR gene expression in MDA-MB453

Project description:The majority of breast cancer subtypes express androgen receptor (AR) in addition to estrogen receptor α (ERα). Depending on the breast cancer subtype androgen signaling has either stimulatory or inhibitory roles in breast cancer cell growth. We have mapped AR cistrome in ERα negative human molecular apocrine breast cancer MDA-MB453 cells and analyzed it in relation to the androgen-regulated transcriptome in the same cells. We have also examined the effect of silencing of the coregulator SUMO ligase PIAS1 on the androgen-regulated transcriptome and AR cistrome in MDA-MB453 cells. Our results show that the MDA-MB453 cells share with VCaP prostate cancer cells a core AR cistrome and target gene signature linked to cancer cell growth and that PIAS1 acts as an AR target gene-selective coregulator in MDA-MB453 cells.

2016-07-18 | GSE70162 | GEO

Chromatin targets of androgen receptor and PIAS1 in molecular apocrine breast cancer cells [ChIP-seq]

Project description:The majority of breast cancer subtypes express androgen receptor (AR) in addition to estrogen receptor a (ERa). Depending on the breast cancer subtype androgen signaling has either stimulatory or inhibitory roles in breast cancer cell growth. We have mapped AR cistrome in ERa negative human molecular apocrine breast cancer MDA-MB453 cells and analyzed it in relation to the androgen-regulated transcriptome in the same cells. We have also examined the effect of silencing of the coregulator SUMO ligase PIAS1 on the androgen-regulated transcriptome and AR cistrome in MDA-MB453 cells. Our results show that the MDA-MB453 cells share with VCaP prostate cancer cells a core AR cistrome and target gene signature linked to cancer cell growth and that PIAS1 acts as an AR target gene-selective coregulator in MDA-MB453 cells.

2016-07-18 | GSE70161 | GEO

DHT-AR, E2-AR and R5020-AR target gene profiles in LNCaP

Project description:We previously encountered regulatory processes where dihydrotestosterone (DHT) exerted its inhibitory effect on parathyroid hormone-related protein (PTHrP) gene repression through the estrogen receptor (ER)M-NM-1, but not the androgen receptor (AR) in breast cancer MCF-7 cells. Here, we investigated whether such an aberrant ligand-nuclear receptor (NR) interaction is present in prostate cancer LNCaP cells. First, we confirmed that LNCaP cells expressed a functional AR and at negligible levels of ERM-NM-1, and progesterone receptors. Both suppression of PTHrP and activation of the PSA genes were observed after treatment of E2, DHT and R5020. Consistent with the previous notion that the AR in LNCaP cells lost the ligand specificity due to a mutation AR (Thr-Ala877), our study using siRNA targeting each NR revealed that the AR, but not the other NRs, monopolized the role as the mediator of shared hormone-dependent regulation. These results were invariably associated with nuclear translocation of this mutant AR. Microarray of the genes regulated by either DHT, E2 or R5020 downstream of the AR (Thr-Ala877) revealed that more than half genes overlapped in LNCaP cells. Noticeably, AR (wild-type, wt) and AR (Thr-Ala877) were equally responsible for the E2-AR interactions. Fluorescent microscopic experiments demonstrated that both EGFP-AR (wt) and EGFP-AR (Thr-Ala877) were exclusively localized within the nucleus after E2 or DHT treatment. Further, a promoter assay revealed that breast cancer MCF-7 and Rv22 cells also exhibited such an aberrant E2-AR (wt) signaling. We postulate entangled interactions between the AR (wt) and E2 in a certain hormone-sensitive cancer cells. Total RNAs from the LNCaP cells transfected with control siRNA (siCT) or siRNA for AR (siAR) transfected LNCaP cells before 24 hr followed by exposed to 10-7M of DHT, E2 or R5020 exposure for another 24 h, respectively, were used.

2014-06-19 | E-GEOD-58615 | biostudies-arrayexpress

Androgen Receptor is a Backdoor Inhibitor of Wildtype and Mutant Estrogen Receptors in Refractory Hormone Receptor-Positive Breast Cancers

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2019-09-19 | GSE128018 | GEO

AR Expression in Breast Cancer CTCs Associates with Bone Metastases

Project description:Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, we undertook RNA sequencing of circulating tumor cells (CTCs) obtained from blood samples of women with metastatic estrogen receptor (ER)+ breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is Androgen Receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splicing variant AR-v7. AR expression within CTCs is correlated with the duration of treatment with aromatase inhibitors, suggesting that it may contribute to acquired resistance to anti-estrogen therapy. In an established breast cancer xenograft model, a bone-tropic derivative displays increased AR expression, whose genetic or pharmacologic suppression reduces metastases to bone but not to lungs. Together, these observations identify AR signaling in CTCs from women with bone-predominant ER+ breast cancer, and provide a rationale for testing androgen inhibitors in this subset of patients.

2018-02-19 | GSE86978 | GEO

DHT-AR, E2-AR and R5020-AR target gene profiles in LNCaP

Project description:We previously encountered regulatory processes where dihydrotestosterone (DHT) exerted its inhibitory effect on parathyroid hormone-related protein (PTHrP) gene repression through the estrogen receptor (ER)α, but not the androgen receptor (AR) in breast cancer MCF-7 cells. Here, we investigated whether such an aberrant ligand-nuclear receptor (NR) interaction is present in prostate cancer LNCaP cells. First, we confirmed that LNCaP cells expressed a functional AR and at negligible levels of ERα, and progesterone receptors. Both suppression of PTHrP and activation of the PSA genes were observed after treatment of E2, DHT and R5020. Consistent with the previous notion that the AR in LNCaP cells lost the ligand specificity due to a mutation AR (Thr-Ala877), our study using siRNA targeting each NR revealed that the AR, but not the other NRs, monopolized the role as the mediator of shared hormone-dependent regulation. These results were invariably associated with nuclear translocation of this mutant AR. Microarray of the genes regulated by either DHT, E2 or R5020 downstream of the AR (Thr-Ala877) revealed that more than half genes overlapped in LNCaP cells. Noticeably, AR (wild-type, wt) and AR (Thr-Ala877) were equally responsible for the E2-AR interactions. Fluorescent microscopic experiments demonstrated that both EGFP-AR (wt) and EGFP-AR (Thr-Ala877) were exclusively localized within the nucleus after E2 or DHT treatment. Further, a promoter assay revealed that breast cancer MCF-7 and Rv22 cells also exhibited such an aberrant E2-AR (wt) signaling. We postulate entangled interactions between the AR (wt) and E2 in a certain hormone-sensitive cancer cells.

2014-06-19 | GSE58615 | GEO

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