Adenosine A1 receptor, a target and regulator of estrogen receptorα action, mediates the proliferative effects of estradiol in breast cancer
Open Access
- 23 November 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 29 (8), 1114-1122
- https://doi.org/10.1038/onc.2009.409
Abstract
Estrogen receptor-α (ERα) and its ligand estradiol (E2) has critical roles in breast cancer growth and are key therapeutic targets. In this study, we report a novel dual role of the adenosine A1 receptor (Adora1) as an E2/ERα target and a regulator of ERα transcriptional activity. In ERα-positive breast cancer cells, E2 upregulated Adora1 messenger RNA (mRNA) and protein levels, an effect that was reversed by the E2 antagonist ICI 182 780. Small interference RNA ablation of Adora1 in ERα-positive cells reduced basal and E2-dependent proliferation, whereas Adora1 over-expression in an ERα-negative cell line induced proliferation. The selective Adora1 antagonist, DPCPX, reduced proliferation, establishing Adora1 as a mediator of E2/ERα-dependent breast cancer growth. Intriguingly, Adora1 ablation decreased both mRNA and protein levels of ERα and, consequently, estrogen-responsive element-dependent ERα transcriptional activity. Moreover, Adora1 ablation decreased binding activity of ERα to the promoter of its target gene TFF1 and led to reduced TFF1 promoter activity and mRNA levels, suggesting that Adora1 is required for full transcriptional activity of ERα on E2 stimulation. Taken together, we showed a short feed-forward loop involving E2, ERα and Adora1 that favors breast cancer growth. These data suggest that Adora1 may represent an important target for therapeutic intervention in hormone-dependent breast cancer.Keywords
This publication has 44 references indexed in Scilit:
- Current controversies in extended adjuvant endocrine therapy for early breast cancerCurrent Opinion in Oncology, 2008
- Tamoxifen Chemoprevention Treatment and Time to First Diagnosis of Estrogen Receptor-Negative Breast CancerJNCI Journal of the National Cancer Institute, 2008
- Up‐regulation of adenosine A1 receptors in frontal cortex from Pick's disease casesEuropean Journal of Neuroscience, 2007
- A1 adenosine receptors play an essential role in protecting the embryo against hypoxiaProceedings of the National Academy of Sciences of the United States of America, 2007
- Adenosine regulation of alveolar fluid clearanceProceedings of the National Academy of Sciences of the United States of America, 2007
- Endocrine therapy resistance can be associated with high estrogen receptor α (ERα) expression and reduced ERα phosphorylation in breast cancer modelsEndocrine-Related Cancer, 2006
- Polyamine Analogues Down-regulate Estrogen Receptor α Expression in Human Breast Cancer CellsPublished by Elsevier BV ,2006
- Chromosome-Wide Mapping of Estrogen Receptor Binding Reveals Long-Range Regulation Requiring the Forkhead Protein FoxA1Cell, 2005
- Sensitization of visceral afferents to bradykinin in rat jejunum in vitroThe Journal of Physiology, 1999
- PD 116,948, a highly selective A1 adenosine receptor antagonistLife Sciences, 1987