title: Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells.
abstract: Lymphangioleiomyomatosis (LAM) is an often fatal disease primarily affecting young women in which tuberin (TSC2)-null cells metastasize to the lungs. The mechanisms underlying the striking female predominance of LAM are unknown. We report here that 17-beta-estradiol (E(2)) causes a 3- to 5-fold increase in pulmonary metastases in male and female mice, respectively, and a striking increase in circulating tumor cells in mice bearing tuberin-null xenograft tumors. E(2)-induced metastasis is associated with activation of p42/44 MAPK and is completely inhibited by treatment with the MEK1/2 inhibitor, CI-1040. In vitro, E(2) inhibits anoikis of tuberin-null cells. Finally, using a bioluminescence approach, we found that E(2) enhances the survival and lung colonization of intravenously injected tuberin-null cells by 3-fold, which is blocked by treatment with CI-1040. Taken together these results reveal a new model for LAM pathogenesis in which activation of MEK-dependent pathways by E(2) leads to pulmonary metastasis via enhanced survival of detached tuberin-null cells.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Yu
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Robb
authors.forename: Tasha A
authors.initials: TA
authors.lastname: Morrison
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ariazi
authors.forename: Magdalena
authors.initials: M
authors.lastname: Karbowniczek
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Astrinidis
authors.forename: Chunrong
authors.initials: C
authors.lastname: Wang
authors.forename: Lisa
authors.initials: L
authors.lastname: Hernandez-Cuebas
authors.forename: Laura F
authors.initials: LF
authors.lastname: Seeholzer
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nicolas
authors.forename: Harvey
authors.initials: H
authors.lastname: Hensley
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Walker
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Henske
mesh_terms: D000818:Animals; D023102:Anoikis / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000502:physiology*; D004967:Estrogens / Q000502:physiology*; D005260:Female; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009362:Neoplasm Metastasis; D010052:Ovariectomy; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D051381:Rats; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D002352:Carrier Proteins; D004967:Estrogens; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases