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Gene Expression Preferentially Regulated by Tamoxifen in Breast Cancer Cells

ABSTRACT: The beneficial effect of the selective estrogen receptor modulator (SERM) tamoxifen in the treatment and prevention of breast cancer is assumed to be through its ability to antagonize the stimulatory actions of estrogen, although tamoxifen can also have some estrogen-like agonist effects. Here we report that in addition to these mixed agonist/antagonist actions, tamoxifen can also selectively regulate a unique set of more than 60 genes in estrogen receptor alpha (ERa)-positive MCF-7 human breast cancer cells which are minimally regulated by estradiol or raloxifene. This gene regulation by tamoxifen is mediated by ERa and is reversed by estradiol or ICI 182,780. We find that the introduction of ERbeta into MCF-7 cells reverses tamoxifen action on approximately 75% of these genes, suggesting that ERbeta is capable of repressing certain actions of tamoxifen. To examine whether these genes might serve as markers of tamoxifen sensitivity and/or the development of resistance, the expression level of these genes was examined in breast tumors of women who had received treatment with tamoxifen. High expression of two of the tamoxifen stimulated genes, YWHAZ/14-3-3z and LOC441453, was found to correlate significantly with disease recurrence following tamoxifen treatment in women with ER-positive tumors, and hence appear to be markers of a poor prognosis. Our data indicate a new dimension in tamoxifen action, involving gene expression regulation that is tamoxifen-preferential, and identify genes that might serve as markers of tumor responsiveness or resistance to tamoxifen therapy. Keywords: ligand response in two ER backgrounds

ORGANISM(S): Homo sapiens

PROVIDER: GSE4025 | GEO | 2006/07/28

SECONDARY ACCESSION(S): PRJNA95129

REPOSITORIES: GEO

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Transcription profiling of human MCF-7 breast cancer cell line transfected with adenovirus expressing Erbeta treated with estrogen or tamoxifen reveals tamoxifen can selectively regulate a unique set of >60 genes, which are minimally regulated by estradiol (E2) or raloxifene.

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