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Increased Mitogen-Activated Protein Kinase Kinase/Extracellularly Regulated Kinase Activity in Human Endometrial Stromal Fibroblasts of Women with Endometriosis Reduces 3',5'-Cyclic Adenosine 5'-Monophosphate Inhibition of Cyclin D1

Department of Obstetrics, Gynecology, and Reproductive Sciences (M.C.V., L.A., L.C.G.), Center for Reproductive Sciences, University of California San Francisco, San Francisco, California 94143; and Department of Obstetrics and Gynecology (C.R.N.), Stanford University, Stanford, California 94024

Address all correspondence and requests for reprints to: Linda C. Giudice, M.D., Ph.D., M.Sc., Professor and Chair, Department of Obstetrics, Gynecology, and Reproductive Sciences, The Robert B. Jaffe, M.D., Endowed Professor in the Reproductive Sciences, University of California, San Francisco, 505 Parnassus Avenue, M1496, Box 0132, San Francisco, California 94143-0132. E-mail: giudice{at}obgyn.ucsf.edu.

Endometriosis is characterized by endometrial tissue growth outside the uterus, due primarily to survival, proliferation, and neoangiogenesis of eutopic endometrial cells and fragments refluxed into the peritoneal cavity during menses. Although various signaling molecules, including cAMP, regulate endometrial proliferation, survival, and embryonic receptivity in endometrium of women without endometriosis, the exact molecular signaling pathways in endometrium of women with disease remain unclear. Given the persistence of a proliferative profile and differential expression of genes associated with the MAPK signaling cascade in early secretory endometrium of women with endometriosis, we hypothesized that ERK1/2 activity influences cAMP regulation of the cell cycle. Here, we demonstrate that 8-Br-cAMP inhibits bromodeoxyuridine incorporation and cyclin D1 (CCND1) expression in cultured human endometrial stromal fibroblasts (hESF) from women without but not with endometriosis. Incubation with serum-containing or serum-free medium resulted in higher phospho-ERK1/2 levels in hESF of women with vs. without disease, independent of 8-Br-cAMP treatment. The MAPK kinase-1/2 inhibitor, U0126, fully restored cAMP down-regulation of CCND1, but not cAMP up-regulation of IGFBP1, in hESF of women with vs. without endometriosis. Immunohistochemistry demonstrated the highest phospho-ERK1/2 in the late-secretory epithelial and stromal cells in women without disease, in contrast to intense immunostaining in early-secretory epithelial and stromal cells in those with disease. These findings suggest that increased activation of ERK1/2 in endometrial cells from women with endometriosis may be responsible for persistent proliferative changes in secretory-phase endometrium.