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Novel Transcriptional Interactions Between the Estrogen and Retinoic Acid Receptors in Human Breast Cancer Cells

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Annual rept. 1 Jun 1999-31 May 2000

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The purpose of this research is to investigate the specific mechanisms by which transcriptional pathways may become more responsive to retinoids in cells that express estrogen receptor ERalpha. Understanding how the steroid hormone receptors interact to control transcription and inhibit growth of cancer cells will suggest directions for the use of retinoids or may provide the foundation for target-oriented therapies in breast cancer. To determine which region of the ER is required for retinoid sensitivity, several deletion mutants of ER were subcloned into a retroviral vector containing an internal ribosomal entry site IRES and green fluorescent protein GFP. Target ER-negative cells were infected with virus containing ER-deletion mutant, ER-wild-type or the empty retroviral control vector. Studies with the deletion mutants indicate that the N-terminal region of ER is required to potentiate the retinoid response. Like ER-positive cells, C-terminal deletion mutants are growth inhibited by retinoids and give a greater than 100 fold induction on a betaRARE compared to the retroviral control. These results indicate that the restored response to RA is mediated by the N-terminal of ERalpha. Blocking the AF1 domain of the ER with ICI diminishes the effect of ER, indicating that phosphorylation and activation of AF1 may play an important role in the cross-talk between ER and RAR pathways.

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  • Medicine and Medical Research

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