title: Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis.
abstract: 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.
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Erik
authors.initials: E
authors.lastname: Zhang
authors.forename: John D
authors.initials: JD
authors.lastname: Mancini
authors.forename: Andrey
authors.initials: A
authors.lastname: Parkhitko
authors.forename: Tasha A
authors.initials: TA
authors.lastname: Morrison
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Henske
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Yu
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D024141:Collagen Type IV / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004958:Estradiol / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000556:secondary*; D018192:Lymphangioleiomyomatosis / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D051381:Rats; D011959:Receptors, Estradiol / Q000037:antagonists & inhibitors; D016019:Survival Analysis; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D024141:Collagen Type IV; D011959:Receptors, Estradiol; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000077267:Fulvestrant; D004958:Estradiol; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse