Genomic antagonism between retinoic acid and estrogen signaling in breast cancer.
Retinoic acid (RA) triggers antiproliferative effects in tumor cells, and therefore RA and its synthetic analogs have great potential as anticarcinogenic agents. Retinoic acid receptors (RARs) mediate RA effects by directly regulating gene expression. To define the genetic network regulated by RARs in breast cancer, we identified RAR genomic targets using chromatin immunoprecipitation and expression analysis. We found that RAR binding throughout the genome is highly coincident with estrogen receptor alpha (ERalpha) binding, resulting in a widespread crosstalk of RA and estrogen signaling to antagonistically regulate breast cancer-associated genes. ERalpha- and RAR-binding sites appear to be coevolved on a large scale throughout the human genome, often resulting in competitive binding activity at nearby or overlapping cis-regulatory elements. The highly coordinated intersection between these two critical nuclear hormone receptor signaling pathways provides a global mechanism for balancing gene expression output via local regulatory interactions dispersed throughout the genome.
Hua
Sujun
S
Institute for Genomics and Systems Biology and Department of Human Genetics, The University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
Kittler
Ralf
R
White
Kevin P
KP
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma
D047628:Estrogen Receptor alpha; D004967:Estrogens; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human