Objectives GPR30 is a 7-transmembrane G protein-coupled estrogen receptor that functions alongside traditional estrogen receptors to regulate cellular responses to estrogen. Recent studies suggest that GPR30 expression is linked to lower survival rates in endometrial and breast cancer. This study was conducted to evaluate GPR30 expression in ovarian tumors. Methods GPR30 expression was analyzed using immunohistochemistry and archival specimens from 45 patients with ovarian tumors of low malignant potential (LMP) and 89 patients with epithelial ovarian cancer (EOC). Expression, defined as above or below the median (intensity times the percentage of positive epithelial cells) was correlated with predictors of adverse outcome and survival. Results GPR30 expression above the median was observed more frequently in EOC than in LMP tumors (48.3% vs. 20%, p= 0.002), and in EOC was associated with lower 5-yr survival rates (44.2% vs. 82.6%, Log rank p < 0.001). Tumor grade and FIGO stage, the other significant predictors of survival, were used to stratify cases into “high-risk” and “low risk” groups. The 5-yr survival rate for “low risk” EOC (all grade 1 and stage I/II, grade 2) was 100%. In “high risk” EOC (all grade 3 and stage III/IV, grade 2), the difference in 5-year survival by GPR 30 expression was significant (33.3% vs. 72.4%, p = 0.001). Conclusions The novel estrogen-responsive receptor GPR30 is preferentially expressed in “high risk” EOC and is associated with lower survival rates. Further investigation of GPR30 as a potential target for therapeutic intervention in high risk EOC is warranted.
SUMMARYRTK/Ras/MAPK signaling pathways play key functions in metazoan development, but how they control expression of downstream genes is not well understood. In Drosophila, it is generally assumed that most transcriptional responses to RTK signal activation depend on binding of Ets-family proteins to specific cis-acting sites in target enhancers. Here, we show that several Drosophila RTK pathways control expression of downstream genes through common octameric elements that are binding sites for the HMGbox factor Capicua, a transcriptional repressor that is downregulated by RTK signaling in different contexts. We show that Torso RTK-dependent regulation of terminal gap gene expression in the early embryo critically depends on Capicua octameric sites, and that binding of Capicua to these sites is essential for recruitment of the Groucho co-repressor to the huckebein enhancer in vivo. We then show that subsequent activation of the EGFR RTK pathway in the neuroectodermal region of the embryo controls dorsal-ventral gene expression by downregulating the Capicua protein, and that this control also depends on Capicua octameric motifs. Thus, a similar mechanism of RTK regulation operates during subdivision of the anterior-posterior and dorsal-ventral embryonic axes. We also find that identical DNA octamers mediate Capicua-dependent regulation of another EGFR target in the developing wing. Remarkably, a simple combination of activator-binding sites and Capicua motifs is sufficient to establish complex patterns of gene expression in response to both Torso and EGFR activation in different tissues. We conclude that Capicua octamers are general response elements for RTK signaling in Drosophila.
Our results provide clinicians, administrators and policy-makers with knowledge of the environmental impact of their decisions to facilitate adoption of sustainable practices.
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