Induction of Retinoid Resistance in Breast Cancer Cells by Overexpression of cjun1

To investigate the role of AP-1 transcription factors in mediating retinoid-induced growth suppression of breast cells, we studied the sensi tivity of MCF7 breast cancer cells with different levels of AP-1 activity to all-frans retinole acid (atRA). AP-1 activity was increased in MCF7 cells by stably transfecting c-jun cDNA into these cells. Parental and vectortransfected MCF7 cells, which were sensitive to the growth-inhibitory effects of atRA, exhibited atRA-dependent retinole acid receptor (RAR) transactivation and transrepression of 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 activity. The c-y'un-transfected MCF7 cells had in creased basal AP-1 transactivation activity and increased expression of AP-1-regulated genes but were resistant to the antiproliferative effects of atRA. However, MCF7 cells transfected with a deletion mutant of c-jun, TAM-67, which lacks most of the ammo-terminal transactivation domain of r.liui and is unable to activate AP-1-dependent gene expression, were sensitive to the growth-inhibitory effects of atRA. These results suggest that the transactivation domain of cjun is required for induction of retinoid resistance in these breast cancer cells. atRA did not activate RAR-dependent gene transcription or transrepress 12-0-tetradecanoylphorbol-13-acetate-induced AP-1 activity in these cjun-overexpressing cells. Investigation of the RAR and retinoic acid X receptor expression level demonstrated that RARa and RARy KNA expression was reduced in the c-j'un-transfected MCF7 cells, whereas RAR/3 expression was upregulated. However, retinoic acid responsive element DNA binding activ ity was intact in c-y'un-transfected cells. Therefore, the mechanism by which cjun overexpression induces resistance to the growth-inhibitory effect of atRA may be through interference with atRA-dependent RAR transactivation or AP-1 transrepression, possibly through titration of essential coactivators. These results suggest that the antiproliferative ef fects of retinoids can be overcome by cjun overexpression.