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

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Retinoids, analogs of Vitamin A, inhibit breast cancer cell 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. 4HP We established an in vitro model by generating two stable retinoid resistant cell lines, MCF-7LCC2O to the 4HPR and MCF-7LCC2l to the 9cis. They were generated through selection of an estrogen independent MCF-7 variant LCCl against increasing concentrations of 4-HPR and 9-cis-RA. Anchorage-dependent growth assays confirm that MCF- 7LCC2O4 to the HPR is stably and consistently 3-5 fold resistant to the drug 4-HPR and shows a half log of cross-resistance to 9-cis-RA. However, MCF-7LCC21 to the 9-cis maintains its resistance to 9-cis-RA 100-fold but exhibits no cross-resistance to 4-HPR. RARalpha and RXRalpha RNA expression in these retinoid resistant cell lines are unaltered with respect to the parental cells. Other receptor isotypes are currently under investigation. We are presently using 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.

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  • Anatomy and Physiology
  • Medicine and Medical Research
  • Pharmacology

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