Activation of the estrogen receptor contributes to the progression of pulmonary lymphangioleiomyomatosis via matrix metalloproteinase-induced cell invasiveness

J Clin Endocrinol Metab. 2008 May;93(5):1625-33. doi: 10.1210/jc.2007-1283. Epub 2008 Feb 19.


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)-alpha and ERbeta analyses were conducted by RT-PCR. ERalpha and ERbeta, 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 (ERalpha and ERbeta), which undergo rapid intracellular turnover in their unbound state. 17beta-estradiol (E(2)) enhances the transcriptional ER activity. E(2)-induced ER activation increases synthesis and activity of MMP-2 through posttranscriptional mechanisms in LAMD-SM. The E(2)/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Disease Progression
  • Estradiol / pharmacology
  • Humans
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / pathology
  • Lymphangioleiomyomatosis / enzymology
  • Lymphangioleiomyomatosis / etiology*
  • Lymphangioleiomyomatosis / pathology
  • Matrix Metalloproteinase 14 / analysis
  • Matrix Metalloproteinase 2 / physiology*
  • Neoplasm Invasiveness
  • Proteasome Endopeptidase Complex / physiology
  • RNA, Messenger / analysis
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / physiology*
  • Tissue Inhibitor of Metalloproteinase-2 / analysis
  • Transcription, Genetic


  • RNA, Messenger
  • Receptors, Estrogen
  • Tissue Inhibitor of Metalloproteinase-2
  • Estradiol
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14
  • Proteasome Endopeptidase Complex