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Activation of the Estrogen Receptor Contributes to the Progression of Pulmonary Lymphangioleiomyomatosis via Matrix Metalloproteinase-Induced Cell Invasiveness

Departments of Medicine and Surgery (M.K.G., S.J.E., J.F., P.C., R.D., M.K.), Miller School of Medicine, University of Miami, Miami, Florida 33136; Cell and Cancer Biology Branch (W.S.-S.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Université de Bordeaux (M.P.), Unité Micronutriments Reproduction Sanité ENITA de Bordeaux, 33175 Gradignan, France

Address all correspondence and requests for reprints to: Marilyn K. Glassberg, M.D., University of Miami Miller School of Medicine, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Room 1014, 1600 N.W. 10th Avenue, Miami, Florida 33136. E-mail: mglassbe{at}med.miami.edu.

Context: The role of estrogens in the pathogenesis of lymphangioleiomyomatosis (LAM), an aggressive and destructive, eventually fatal lung disease of women, is poorly understood.

Objective: The study was conducted to test the hypothesis that the lung disease in LAM is estrogen mediated and to determine whether estrogens contribute to the invasiveness of LAM.

Design: In vitro cell culture of spindle-shaped LAM cells (LAMD-SM) were isolated and propagated from affected lungs. Estrogen receptor (ER)- and ERβ analyses were conducted by RT-PCR. ER and ERβ, tissue inhibitor of metalloproteinase-2, and matrix metalloproteinases (MMP)-2 had Western blot analysis for protein assessment. Activity assays were performed for MT1-MMP, MMP-2, and tissue inhibitor of metalloproteinase-2. Assessment of MMP-2 promoter function was done via transfection assays. Cell invasion chambers were used to determine and quantitate cell invasiveness.

Setting: The study was conducted at an academic medical center.

Patients: Tissue and cells were obtained from patients as outlined in approved institution review board protocol (97/007).

Intervention: LAMD-SM cells were treated with a specific MMP-2 antibody or a nonspecific inhibitor, doxycycline.

Main Outcome Measures: Activity of MMP-2 and invasiveness of LAMD-SM cells were measured.

Results: LAMD-SM cells express functional ERs (ER and ERβ), which undergo rapid intracellular turnover in their unbound state. 17β-Estradiol (E₂) enhances the transcriptional ER activity. E₂-induced ER activation increases synthesis and activity of MMP-2 through posttranscriptional mechanisms in LAMD-SM. The E₂/ER-mediated increase of MMP-2 promotes LAMD-SM invasiveness, in assays in vitro, which can be inhibited by specific antibodies against MMP-2 or doxycycline, an inhibitor of MMPs.

Conclusion: The invasion and destruction of lung parenchyma in LAM is, at least partially, an estrogen-MMP-driven process, which has major implications for therapeutic interventions.