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

The role of retinoic acid receptor (RAR) expression in sensitivity to N‐(4‐hydroxyphenyl)retinamide (4HPR or fenretinide) as well as on the tumorigenicity of human ovarian carcinoma cells was examined. Two human ovarian cancer cell lines, A2780 and IGROV‐1, with a 10‐fold difference in sensitivity to 4HPR were chosen to study RAR involvement in the response to 4HPR. To determine which RAR was effective, RARα, β and γ were individually overexpressed in A2780 cells, which are the most sensitive to 4HPR. Sensitivity to 4HPR was increased in RARβ‐overexpressing clones, whereas it was slightly decreased in RARα transfectants (which had diminished RARβ expression) and was unchanged in clones transfected with RARγ. IGROV‐1 cells, which are RARβ negative, were transfected with RARβ. Surprisingly, none of the obtained IGROV‐1 RARβ transfectants expressed RARβ protein, in spite of RARβ mRNA transcription. All clones were similar to the parental IGROV‐1 cells in their sensitivity to 4HPR. Treatment with a pharmacologically achievable concentration of 4HPR (1 μM) led to a rapid 2‐fold increase in RARβ mRNA levels in A2780 cells, but it did not induce RARβ expression in IGROV‐1 cells. Analysis of the tumorigenicity of A2780‐transfected clones revealed that overexpression of RARα was associated with a significant reduction in tumor takes (50% and 67%, respectively, vs. 96% for the parent line) and with a reduced growth rate. Oncogenicity was clearly decreased in only 1 of the 2 RARβ‐overexpressing clones (33% takes) and was unchanged in the 2 clones with increased RARγ expression. Our results demonstrate that basal expression and 4HPR inducibility of RARβ play a role in mediating 4HPR response in ovarian cancer cells. The findings of reduced oncogenicity of clones overexpressing RARα and of one clone overexpressing RARβ indicate that RARα and RARβ might have a tumor‐suppressive effect in ovarian tumors. Int. J. Cancer 81:829–834, 1999. © 1999 Wiley‐Liss, Inc.