The Role of RARalpha Coregulators in Resistance to Vitamin A and Synthetic Retinoids
Abstract
Retinoids, analogs of Vitamin A, inhibit breast cancer cell proliferation through receptors in the super-family of nuclear transcriptional factors. 9-cis retinoic acid (9-cis-RA) is a retinoid pan agonist that activates both RAR and RXR isoforms. N-(4-hydroxyphenyl) retinamide (4-HPR) has unclear receptor selectivity, but shows promising clinical activity. No established in vitro model, however, has been developed to study the problem of acquired retinoid resistance for breast cancer patients. We established an in vitro model by generating two stable retinoid resistant cell lines, MCF-7/LCC20(sup 4-HPR) and MCF-7/LCC21(sup 9-cis-RA). They were generated through selection of an estrogen independent MCF-7 variant (LCC1) against increasing concentrations of 4-HPR and 9-cis-RA. MCF-7/LCC20(sup 4-HPR) is stably resistant to the drug 4-HPR and shows cross-resistance to 9-cis-RA. However, MCF-7/LCC21(sup 9-cis-RA) maintains its resistance to 9-cis-RA but exhibits no cross-resistance to 4-HPR. RAR alpha, RXR beta, and RAR gamma RNA expression in these retinoid resistant cell lines are unaltered with respect to the parental cells, and there is a 50% reduction in the RXR alpha expression of LCC21(sup 9-cis-RA from the parental cell line. RAR beta appears not to be present in parental or resistant cell lines. Several genes have been identified with cDNA microarrays to identify molecular pathways, and the data from the arrays should help identify genes that contribute to the acquired resistance to retinoids in breast cancer cells and should develop neural network classifiers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA400081
Entities
People
- Richard Y. Lee
Organizations
- Georgetown University