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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. Keywords: actions of tamoxifen

ORGANISM(S): Homo sapiens

PROVIDER: GSE3013 | GEO | 2005/07/29

SECONDARY ACCESSION(S): PRJNA93193

REPOSITORIES: GEO

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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.

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Actions of tamoxifen in the uterus and its molecular effectors in endometrial carcinogenesis.

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