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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. 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).

ORGANISM(S): Homo sapiens

SUBMITTER: Narayanan Ramesh

PROVIDER: S-ECPF-GEOD-58196 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Vasculogenic mimicry (VM) with the pattern of endothelial independent tubular structure formation lined by aggressive tumor cells mimics regular tumor blood vessels to ensure robust blood supply and correlates with the proliferation, invasion, metastasis, and poor prognosis of malignant tumors, which was demonstrated to be a major obstacle for resistance to antiangiogenesis therapy. Therefore, it is urgent to discover methods to abrogate the VM formation of tumors, which possesses important practical significance for improving tumor therapy. Brucine is a traditional medicinal herb extracted from seeds of Strychnos nux-vomica L. (Loganiaceae) exhibiting antitumor activity in a variety of cancer models. In the present study, the effect of brucine on vasculogenic mimicry and the related mechanism are to be investigated. We demonstrated that, in a triple-negative breast cancer cell line MDA-MB-231, brucine induced a dose-dependent inhibitory effect on cell proliferation along with apoptosis induction at higher concentrations. The further study showed that brucine inhibited cell migration and invasion with a dose-dependent manner. Our results for the first time indicated that brucine could disrupt F-actin cytoskeleton and microtubule structure, thereby impairing hallmarks of aggressive tumors, like migration, invasion, and holding a possibility of suppressing vasculogenic mimicry. Hence, the inhibitory effect of brucine on vasculogenic mimicry was further verified. The results illustrated that brucine significantly suppressed vasculogenic mimicry tube formation with a dose-dependent effect indicated by the change of the number of tubules, intersections, and mean length of tubules. The in-depth molecular mechanism of vasculogenic mimicry suppression induced by brucine was finally suggested. It was demonstrated that brucine inhibited vasculogenic mimicry which might be through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2 and matrix metalloproteinase-2 and metalloproteinase-9.

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

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