Role of retinoic acid receptor overexpression in sensitivity to fenretinide and tumorigenicity of human ovarian carcinoma cells

dThe role of retinoic acid receptor (RAR) expression in sensitivity to N-(4 -hydroxyphenyl)retinamide (4HPR or fenretinide) as well as on the tumorigen icity of human ovarian carcinoma cells was examined. Two human ovarian canc er cell lines, A2780 and IGROV-I, with a 10-fold difference in sensitivity to 4HPR were chosen to study RAR involvement in the response to 4HPR. To de termine which RAR was effective, RAR alpha, beta and gamma were individuall y overexpressed in A2780 cells, which are the most sensitive to 4HPR. Sensi tivity to 4HPR was increased in RAR beta-overexpressing clones, whereas it was slightly decreased in RAR alpha transfectants (which had diminished RAR beta expression) and was unchanged in clones transfected with RAR gamma. I GROV-I cells, which are RAR beta negative, were transfected with RAR beta. Surprisingly, none of the obtained IGROV-I RAR beta transfectants expressed RAR beta protein, in spite of RAR beta mRNA transcription. All clones were similar to the parental IGROV-I cells in their sensitivity to 4HPR. Treatm ent with a pharmacologically achievable concentration of 4HPR (I mu M) led to a rapid 2-fold increase in RAR beta mRNA levels in A2780 cells, but it d id not induce RAR beta expression in IGROV-I cells. Analysis of the tumorig enicity of A2780-transfected clones revealed that overexpression of RARa wa s associated with a significant reduction in tumor takes (50% and 67%, resp ectively, vs. 96% for the parent line) and with a reduced growth rate. Onco genicity was clearly decreased in only I of the 2 RAR beta-overexpressing c lones (33% takes) and was unchanged in the 2 clones with increased RAR gamm a expression. Our results demonstrate that basal expression and 4HPR induci bility of RAR beta play a role in mediating 4HPR response in ovarian cancer cells. The findings of reduced oncogenicity of clones overexpressing RAR a lpha and of one clone overexpressing RAR beta indicate that RAR alpha and R AR beta might have a tumor-suppressive effect in ovarian tumors. Int. j. Ca ncer 81:829-834, 1999. (C) 1999 Wiley-Liss, Inc.