Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of endometrial epithelial cells (EECs) to understand actions of tamoxifen in the uterus and its molecular effectors in endometrial carcinogenesis

ABSTRACT: The molecular explanation for tamoxifen serving as a breast cancer treatment but displaying partial estrogenic in the uterus is not known. Previously, we reported that differential promoter context and cofactor recruitment contribute to the tissue specificity of tamoxifen. Here, we investigated the genomic basis for the partial oestrogenic activity of tamoxifen in the endometrium. We showed that tamoxifen not only affects the rate of transcription of oestrogen target genes but also targets a unique set of genes. Since oestrogen and tamoxifen are both able to bind to oestrogen receptors (ERs) and because both promote endometrial carcinogenesis, we hypothesized that the molecular effectors for ERs in endometrial carcinogenesis most likely reside in genes that are commonly targeted by oestrogen and tamoxifen. Among those target genes, we identified a paired-box gene PAX2 that is critically involved in cell proliferation and carcinogenesis in the endometrium. Our experiments also demonstrated that PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and this activation is associated with cancer-linked hypomethylation of the PAX2 promoter. Experiment Overall Design: each experiment repeat 2 times.

ORGANISM(S): Homo sapiens

DISEASE(S): endometrioid carcinoma

SUBMITTER: Yongfeng Shang

PROVIDER: E-GEOD-3013 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis.

Wu Huijian H Chen Yupeng Y Liang Jing J Shi Bin B Wu Ge G Zhang Ying Y Wang Dan D Li Ruifang R Yi Xia X Zhang Hua H Sun Luyang L Shang Yongfeng Y

Nature 20051201 7070

Tamoxifen, a selective oestrogen receptor modulator, has been used in the treatment of all stages of hormone-responsive breast cancer. However, tamoxifen shows partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial cancer. The molecular explanation for these observations is not known. Here we show that tamoxifen and oestrogen have distinct but overlapping target gene profiles. Among the overlapping target genes, we identify a paired- ...[more]

PMID: 16355216

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Project description:Global gene expression patterns associated with early stage endometrial cancer have been reported, but changes in molecular expression associated with tumor grade, depth of myometrial invasion, and non-endometrioid histology have not been previously elucidated. Our group hypothesized there are unique genetic events underlying early endometrial carcinogenesis. Ninety-two samples of pathologically reviewed stage I endometrial cancers (80 endometrioid and 12 serous) with a heterogeneous distribution of grade and depth of myometrial invasion (i.e. 9 IAG1, 14 IAG2, 7 IAG3, 14 IBG1, 12 IBG2, 13 IBG3, 7 ICG1, 10 ICG2, and 6 ICG3) were examined in relation to 12 samples of atrophic endometrium from postmenopausal women. Specimens were analyzed using oligonucleotide microarray analysis and a subset of the differentially expressed transcripts was validated using quantitative PCR. Comparison of early stage cancers with normal endometrium samples by the univariate t-test with 10,000 permutations identified 900 genes that were differentially regulated by at least 4-fold at a p value of <0.001. Unsupervised analysis revealed that when compared to normal endometrium, serous and endometrioid stage I cancers appeared to have similar expression patterns. However, when compared in the absence of normal controls, they were distinct. Differential expression analysis revealed a number of transcripts that were common as well as unique to both histologic types. This data uncovers previously unrecognized, novel pathways involved in early stage endometrial cancers and identifys targets for prevention strategies that are inclusive of both endometrioid and serous histologic subtypes. Ninety-one samples of pathologically reviewed stage I endometrial cancers (79 endometrioid and 12 serous) with a heterogeneous distribution of grade and depth of myometrial invasion (i.e. 9 IAG1, 14 IAG2, 7 IAG3, 14 IBG1, 12 IBG2, 13 IBG3, 7 ICG1, 10 ICG2, and 6 ICG3) were examined in relation to 12 samples of atrophic endometrium from postmenopausal women. Specimens were analyzed using oligonucleotide array analysis.

Dataset Information

Transcription profiling of endometrial epithelial cells (EECs) to understand actions of tamoxifen in the uterus and its molecular effectors in endometrial carcinogenesis

Publications

Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis.

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