Accession Number : ADA300281

Title :   Gene Activation by Antiestrogens Used in Breast Cancer Therapy via the Interaction of the Estrogen Receptor and AP-1.

Descriptive Note : Annual rept. 1 Jul 94-30 Jun 95,

Corporate Author : CALIFORNIA UNIV SAN FRANCISCO

Personal Author(s) : Kushner, Peter J.

PDF Url : ADA300281

Report Date : 21 JUL 1995

Pagination or Media Count : 43

Abstract : We find that tamoxifen is a potent activator of estrogen receptor (ER) mediated induction of promoters regulated by AP- 1 sites. This contrasts with the inability of tamoxifen to activate otherwise identical promoter constructs bearing a classical ERE. Tamoxifen agonism at AP- 1 sites is cell type specific occurring in cell lines of uterine origin but not of breast origin. It thus parallels tamoxifen agonism in vivo. AP-l proteins such as Jun or Jun/Fos are needed for tamoxifen stimulation, which appears to increase the transcriptional efficiency of these proteins even when they are provided at optimal amounts. The DNA binding domain (DBD) of ER is required for tamoxifen activation at AP-1 sites whereas estrogen activation is mostly independent of this domain. This suggests the existence of two pathways of ER action at AP-1: an CL (DBD dependent) pathway activated by tamoxifen, and a B (DED independent) pathway activated only by estrogen. Fusing VPl6 transcriptional activation functions to ER super-potentiates the B, but not the CL, pathway. We discuss models for the two pathways and the implications of these results.

Descriptors :   *THERAPY, *GENES, *CANCER, *ESTROGENS, *BREAST CANCER, STIMULATION(GENERAL), CELLS, PROTEINS, DEOXYRIBONUCLEIC ACIDS, IN VIVO ANALYSIS, SENSE ORGANS, MAMMARY GLANDS.

Subject Categories : Medicine and Medical Research
      Genetic Engineering and Molecular Biology

Distribution Statement : APPROVED FOR PUBLIC RELEASE