Role of RARalpha Coregulators in Resistance to Vitamin A and Synthetic Retinoids

摘要

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/LCC2O to the 4HPR and MCF-7/LCC21 to the 9CIS. 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 to the 4HPR is stably resistant to the drug 4- HPR and shows cross-resistance to 9-cis-RA. However, MCF-7/LCC21 to the 9CIS maintains its resistance to 9-cis-RA but exhibits no cross-resistance to 4-HPR. RARa and RARy RNA expression in these retinoid resistant cell lines are unaltered with respect to the parental cells, and there is a 50% reduction in the RXRa expression of LCC21 to the 9CIS from the parental cell line. Other receptor isotypes are currently under investigation. 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 acquired resistance to retinoids in breast cancer cells.