RETINOID REFRACTORINESS OCCURS DURING LUNG CARCINOGENESIS DESPITE FUNCTIONAL RETINOID RECEPTORS

Retinoids have demonstrated activity in the prevention of second prima ry tumors in patients with non-small cell lung cancer (NSCLC). They al so contribute to the normal growth and differentiation of human bronch ial epithelial (HBE) cells. Because retinoids mediate their actions th rough retinoid nuclear receptors (RARs and RXRs), aberrant signaling t hrough retinoid receptors could contribute to lung carcinogenesis. Usi ng a lung carcinogenesis model consisting of normal, premalignant, and malignant HBE cells, we examined all-trans retinoic acid (t-RA)-induc ed changes in cellular growth. These studies revealed that t-RA treatm ent inhibited the growth of normal HBE cells, but premalignant and mal ignant HBE cells were relatively resistant to t-RA. Coincident with th e development of retinoid refractoriness, basal expression of the reti noic acid nuclear receptor beta (RAR-beta) increased. Analysis of rece ptor function by gel shift and transient transfection assays of normal , premalignant, and malignant HBE cells demonstrated that receptor-DNA binding and transcriptional activation properties were intact in the t-RA-refractory malignant HBE cells. To compare these findings to NSCL Cs in patients, we investigated retinoid receptor expression in NSCLC biopsies. A subset of the tumors expressed RAR-beta, reflecting the RA R-beta expression observed in the malignant HBE cells in culture. Thes e findings demonstrate that retinoid receptor function was intact in t he t-RA-refractory malignant HBE cell line, suggesting that the defect in retinoid signaling in this lung carcinogenesis model is not intrin sic to the retinoid receptors.