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Human Uterine Smooth Muscle and Leiomyoma Cells Differ in Their Rapid 17β-Estradiol Signaling: Implications for Proliferation

Center for Bioenvironmental Research (E.N.N.-S., M.M.M., T.-C.C., L.I.M., J.A.M.), Tulane University, and Tulane Cancer Center (E.N.N.-S., M.E.B., J.A.M.), Departments of Microbiology (L.I.M.) and Pharmacology (M.E.B., J.A.M.), and Department of Medicine (L.V.R., S.E.M., M.E.B.), Section of Hematology and Medical Oncology, Tulane Medical School, New Orleans, Louisiana 70112; and Laboratory of Molecular Pharmacology (M.M.M.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. John A. McLachlan, Center for Bioenvironmental Research, Tulane Medical School, New Orleans, Louisiana 70118. E-mail: jmclach{at}tulane.edu.

Uterine leiomyomas, benign uterine smooth muscle tumors that affect 30% of reproductive-aged women, are a significant health concern. The initiation event for these tumors is unclear, but 17β-estradiol (E2) is an established promoter of leiomyoma growth. E2 not only alters transcription of E2-regulated genes but also can rapidly activate signaling pathways. The aim of our study is to investigate the role of rapid E2-activated cytoplasmic signaling events in the promotion of leiomyomas. Western blot analysis revealed that E2 rapidly increases levels of phosphorylated protein kinase C (PKC) in both immortalized uterine smooth muscle (UtSM) and leiomyoma (UtLM) cell lines, but increases levels of phosphorylated ERK1/2 only in UtLM cells. Our studies demonstrate a paradoxical effect of molecular and pharmacological inhibition of PKC on ERK1/2 activation and cellular proliferation in UtLM and UtSM cells. PKC inhibition decreases levels of phosphorylated ERK1/2 and proliferation in UtLM cells but raises these levels in UtSM cells. cAMP-PKA signaling is rapidly activated only in UtSM cells with E2 and inhibits ERK1/2 activation and proliferation. We therefore propose a model whereby E2’s rapid activation of PKC and cAMP-PKA signaling plays a central role in the maintenance of a low proliferative index in normal uterine smooth muscle via its inhibition of the MAPK cascade and these pathways are altered in leiomyomas to promote MAPK activation and proliferation. These studies demonstrate that rapid E2-signaling pathways contribute to the promotion of leiomyomas.

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