Ribozyme targeting demonstrates that the nuclear receptor coactivator AIB1is a rate-limiting factor for estrogen-dependent growth of human MCF-7 breast cancer cells

Human breast tumorigenesis is promoted by the estro gen receptor pathway, a nd nuclear receptor coactivators are thought to participate in this process . Here we studied whether one of these coactivators, AIB1 (amplified in bre ast cancer (1) under bar), was rate-limiting for hormone-dependent growth o f human MCF-7 breast cancer cells. We developed MCF-7 breast cancer cell li nes in which the expression of AIB1 can be modulated by regulatable ribozym es directed against AIB1 mRNA, We found that depletion of endogenous AIB1 l evels reduced steroid hormone signaling via the estrogen receptor Lu or pro gesterone receptor p on transiently transfected reporter templates. Down-re gulation of AIB1 levels in MCF-7 cells did not affect estrogen-stimulated c ell cycle progression but reduced estrogen-mediated inhibition of apoptosis and cell growth. Finally, upon reduction of endogenous AIB1 expression, es trogen-dependent colony formation in soft agar and tumor growth of MCF-7 ce lls in nude mice was decreased. From these findings we conclude that, despi te the presence of different estrogen receptor coactivators in breast cance r cells, AIB1 exerts a rate-limiting role for hormone-dependent hu. man bre ast tumor growth.