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An Adenosine Analogue, IB-MECA, Down-Regulates Estrogen Receptor and Suppresses Human Breast Cancer Cell Proliferation¹

Department of Biochemistry and Cancer Center, Boston University School of Medicine, Boston, Massachusetts 02118

Adenosine, a natural metabolite, plays important roles in several physiological and pathological processes, including modulation of cellular proliferation. Here, we report that among different adenosine analogues tested, micromolar concentrations of the A₃ adenosine receptor (A₃AR)-selective agonist N⁶-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) completely inhibited the growth of the human breast cancer cell lines MCF-7 and ZR-75 while inducing apoptosis in T47D and Hs578T cells, which do not express A₃AR mRNA. In MCF-7 cells, A₃AR overexpression did not increase the sensitivity to drug treatment and an A₃AR antagonist did not abolish IB-MECA effect. In search for mechanisms of the effect of this ligand, we found that in estrogen receptor (ER)-positive cells, IB-MECA rapidly down-regulated ER at mRNA and protein levels and consequently at the transcriptional activity level. Moreover, overexpression of ER in MCF-7 cells alleviated the proliferation inhibition induced by IB-MECA. The inhibitory effects on cell growth and to some extent on ER were mimicked by 2-chloro-adenosine >3'-deoxyadenosine> adenosine but not by a variety of other ligands. Our studies indicate that IB-MECA can down-regulate ER and inhibit proliferation or induce apoptosis in different breast cancer cell types and raise the possibility of using this and related compounds in breast cancer treatment.

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