MECHANISMS OF ESTROGEN BIOSYNTHESIS IN ENDOMETRIOSIS

Northwestern University At Chicago, Evanston IL

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Abstract

DESCRIPTION (provided by applicant): During the previous funding period, we uncovered a positive feedback cycle that favors aberrant overexpression of STAR, P450arom and COX-2 in the pathologic endometriosis tissue. StAR-P450arom pathway-derived estradiol stimulates COX-2 expression, whereas COX-2-derived PGE2 induces StAR and P450arom expression via cAMP. The clinical relevance was exemplified by the recent and successful use of aromatase inhibitors to treat endometriosis. We generated the following preliminary data: (i) StAR and P450arom are the key steroidogenic genes that mediate PGE2-dependent estradiol formation in endometriosis-derived stromal cells. (ii) Multiple fail-safe mechanisms including inhibitory transcription factors (e.g., COUP-TF) and corepressors (e.g., WT-1) in normal endometrial stromal cells render these cells nonresponsive to PGE2 or cAMP analogs and silence StAR and P450arom promoters. (iii) In endometriotic stromal cells, the aberrantly expressed transcriptional enhancer SF-1 mediates PGE2- dependent induction of multiple steroidogenic promoters (e.g., StAR and P450arom), whereas transcriptional repressors are downregulated. (iv) IL-1beta, PGE2 itself, estradiol and VEGF stimulate COX-2 in endometriotic stromal and uterine endothelial cells. We hypothesize that PGE2 induces (via cAMP) binding of homologous enhancer-type multimeric transcriptional complexes that share common factors to key steroidogenic promoters in endometriotic stromal cells. The key mechanism for steroidogenesis in endometriosis is the aberrant presence of SF-1 that is the critical factor for assembling these stimulatory complexes. We propose the following aims: 1- To determine in vivo distribution of StAR and estradiol levels in endometriosis tissues and characterize PGE2-mediated STAR, protein and mRNA levels in endometriotic stromal cells. 2 - To identify common cis-acting elements, transcriptional factors and co-regulators responsible for PGE2- mediated co-activation of StAR and P450arom promoters in endometriotic cells. 3 - To define in situ composition of multimeric complexes responsible for PGE2-dependent co-activation of key steroidogenic promoters in endometriotic cells. 4 - To determine the molecular mechanisms responsible for SF-1 expression in endometriotic stromal cells. Investigation of local feedback mechanisms responsible for interactions between estrogen biosynthesis, tissue growth, and inflammation will lead to the rational design of novel drug treatments.