Effect of 9-cis-retinoic acid on the functional expression of NIS gene in cultured human breast cancer cells

Objective: To investigate the effect of 9-cis-retinoic acid (9-cis-RA) on the functional expression of sodium/iodide symporter (NIS) in cultured human breast cancer cells. Methods: Two breast cancer cell lines including estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 were incubated with different doses (10-8, 10-7 or 10-6 mol/L) of either 9-cis-RA or all-trans-retinoic acid (ATRA) for various durations (0-44 h). Total RNA was isolated, and then reverse transcription-polymerase chain reaction (RT-PCR) was performed to measure the expression levels of NIS mRNA. 131I uptake was determined in breast cancer cells after treated with RA under the same culture condition for expression of NIS transport. Results: RT-PCR analysis revealed a dose-dependent induction effect on the expression of NIS mRNA in MCF-7 cells exposed to 9-cis-RA (F=114.17, P<0.001). The maximal up-regulation of NIS mRNA expression appeared at 16 h after treated with 9-cis-RA (10-6 mol/L), which was 8.2 times higher than that of control (q=8.32, P<0.01). Moreover, 9-cis-RA (10-6 mol/L, 24 h) enhanced NIS mRNA expression more effectively than ATRA (t = 6.572, P< 0.01). No expression of NIS mRNA was detected in untreated MDA-MB-231 cells; however, unregulated NIS mRNA expression was induced after incubation with 9-cis-RA (10-6 mol/L) but the expression was far lowered than MCF-7(t =20.195, P <0.001). As to the 131I uptakes it increased in MCF-7 cells at 12 h and reached to the maximum at 24 h (3.2-fold over that of baseline) after treated with 10-6 mol/L 9-cis-RA. Also, 131I uptake could be blocked by 3 x 10-5 mol/L KClO4, a specific inhibitor of NIS. Conclusion: 9-cis-RA can significantly enhance the functional expression of NIS and increase the uptake of 131I in ER-positive MCF-7 human breast cancer cells. (authors)