Lymphangioleiomyomatosis (
LAM) is a destructive
lung disease primarily affecting women. Genetic studies indicate that
LAM cells carry inactivating
tuberous sclerosis complex (TSC)-2 mutations, and metastasize to the lung. We previously discovered that
estradiol increases the
metastasis of TSC2-deficient cells in mice carrying xenograft
tumors. Here, we investigate the molecular basis underlying the
estradiol-induced lung
metastasis of TSC2-deficient cells, and test the efficacy of
Faslodex (an
estrogen receptor antagonist) in a preclinical model of
LAM. We used a xenograft
tumor model in which
estradiol induces the lung
metastasis of TSC2-deficient cells. We analyzed the impact of
Faslodex on
tumor size, the extracellular matrix organization, the expression of
matrix metalloproteinase (MMP)-2, and lung
metastasis. We also examined the effects of
estradiol and
Faslodex on MMP2 expression and activity in
tuberin-deficient cells in vitro.
Estradiol resulted in a marked reduction of
Type IV collagen deposition in xenograft
tumors, associated with 2-fold greater MMP2 concentrations compared with placebo-treated mice.
Faslodex normalized the
Type IV collagen changes in xenograft
tumors, enhanced the survival of the mice, and completely blocked lung
metastases. In vitro,
estradiol enhanced MMP2 transcripts,
protein accumulation, and activity. These
estradiol-induced changes in MMP2 were blocked by
Faslodex. In TSC2-deficient cells,
estradiol increased MMP2 concentrations in vitro and in vivo, and induced extracellular matrix remodeling.
Faslodex inhibits the
estradiol-induced lung
metastasis of TSC2-deficient cells. Targeting
estrogen receptors with
Faslodex may be of efficacy in the treatment of
LAM.