Induction of retinoid resistance in breast cancer cells by overexpression of cJun.
To investigate the role of AP-1 transcription factors in mediating retinoid-induced growth suppression of breast cells, we studied the sensitivity of MCF7 breast cancer cells with different levels of AP-1 activity to all-trans retinoic acid (atRA). AP-1 activity was increased in MCF7 cells by stably transfecting c-jun cDNA into these cells. Parental and vector-transfected MCF7 cells, which were sensitive to the growth-inhibitory effects of atRA, exhibited atRA-dependent retinoic acid receptor (RAR) transactivation and transrepression of 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 activity. The c-jun-transfected MCF7 cells had increased 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 amino-terminal transactivation domain of cJun 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-O-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 RAR alpha and RAR gamma RNA expression was reduced in the c-jun-transfected MCF7 cells, whereas RAR beta expression was up-regulated. However, retinoic acid responsive element DNA binding activity was intact in c-jun-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 effects of retinoids can be overcome by cJun overexpression.
Yang
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L
Department of Medicine, University of Texas Health Science Center at San Antonio, 78284, USA.
Kim
H T
HT
Munoz-Medellin
D
D
Reddy
P
P
Brown
P H
PH
D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D017930:Genes, Reporter; D016758:Genes, jun; D006801:Humans; D007700:Kinetics; D016133:Polymerase Chain Reaction; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000633:toxicity*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D016755:Proto-Oncogene Proteins c-jun; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C082925:retinoic acid receptor beta; D014212:Tretinoin; D013755:Tetradecanoylphorbol Acetate