Gene Activation by Antiestrogens Used in Breast Cancer Therapy Via the Interaction of Estrogen Receptor and AP-1
Abstract
Estrogen receptor stimulates target genes that have AP-1 sites with both estrogens and antiestrogens. We examined the role of ER transactivation functions (AF-1 and AF-2) in these responses. Estrogen activation requires ER transactivation functions, and may be obtained with the isolated ER alpha ligand binding domain. In contrast, tamoxifen activation requires the ER B region and is suppressed by AF-1. ER alpha truncations that delete AF-1 enhance tamoxifen action at AP-l, allow even more potent activation by raloxifene and ICI 182,780, and enhance APl activity in response to antiestrogens in a breast cell line. These phenotypes resemble ER beta, which naturally lacks constitutive AF-1 activity and strongly enhances AP-1 activity in the presence of antiestrogens. In every case, antiestrogen effects are independent of intact AF-2. Thus, estrogen activation at AP-1 sites involves the same transactivation functions, AF-1 and AF-2, that mediate classical response, but antiestrogen activation does not utilize these functions, and thus does not resemble conventional transactivation. We conclude that ER activates at AP-1 sites by different mechanisms with estrogens and antiestrogens, and we suggest a model of such activation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 1999
- Accession Number
- ADA371192
Entities
People
- Peter Kushner
Organizations
- University of California, San Francisco