The induction and activation of STAT1 by all-trans-retinoic acid are mediated by RAR beta signaling pathways in breast cancer cells

Retinoic acid receptor-beta (RAR beta) and signal transducer and activator of transcription 1 (STAT1) are important mediators of the antiproliferative and apoptotic actions of retinoids and cytokines/growth factors, respectiv ely. Expression of both RAR beta and STAT1 is lost in most breast cancer ce ll lines but it can be induced by retinoids in estrogen receptor-positive c ells, We investigated a possible functional connection between these two me diators and present evidence supporting RAR beta as a tumor suppressor. Fir st, by using different receptor-selective retinoids, we demonstrated that R AR beta induction in MCF-7 cells by all-trans-retinoic acid (atRA) was asso ciated with the activation of STAT1 gene transcription. The direct involvem ent of RAR beta in atRA-induced STAT1 gene activation was further demonstra ted by showing that transfection with an anti-sense RAR beta construct bloc ked atRA-induced STAT1 expression in MCF-7 cells whereas introduction of a sense-RAR beta construct resulted in STAT1 induction by atRA in MDA-MB 231 cells. In addition, we showed that STAT1 was phosphorylated/activated under atRA treatment of MCF-7 cells; this process required the involvement of RA R beta and protein synthesis. STAT1 phosphorylation/ activation was accompa nied by increased tyrosine kinase activity that was not due to the activati on of JAK1, JAK2 or Tyk 2, suggesting the possible involvement of an uniden tified tyrosine kinase.