Mechanism of Retinoid Response in Human Breast Cancer.
Abstract
The anti-cancer effects of all-trans-retinoic acid (trans-RA) are mainly seen in estrogen-dependent breast cancer cells and that, upon progression of the disease to estrogen independence, breast cancer cells become refractory to trans-RA. Our data demonstrate that a class of RXR- selective retinoids effectively inhibit the growth and induce apoptosis of estrogen-independent breast cancer cells, whereas RAR-selective retinoids only inhibit the growth of estrogen-dependent breast cancer cells. The effects of RXR-selective retinoids are mediated by RXR/nur77 heterodimers that induce RAR expression through binding to a RA response element (beta-RARE) in the RAR-beta promoter. Overexpression of RAR-beta as seen in estrogen-dependent cells, can suppress RXR-selective retinoid effect due to the formation of RARIRXR heterodimers. In addition, orphan receptor COUP-TF may regulate RXR-selective retinoid activities through nur77-COUP-TF interaction. These results demonstrate a novel growth inhibition pathway for trans-RA-resistant, estrogen-independent breast cancer cells. Our studies also show that inhibition of AP-1 activity represents another important mechanism by which retinoids inhibit breast cancer development. Furthermore, we observed that a cell survival gene could regulate retinoid activity in breast cancer cells through protein-protein interaction.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1997
- Accession Number
- ADA337855
Entities
People
- Xiao-kun Zhang
Organizations
- Sanford Burnham Prebys Medical Discovery Institute