Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells.
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.
Yu
Jane J
JJ
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Robb
Victoria A
VA
Morrison
Tasha A
TA
Ariazi
Eric A
EA
Karbowniczek
Magdalena
M
Astrinidis
Aristotelis
A
Wang
Chunrong
C
Hernandez-Cuebas
Lisa
L
Seeholzer
Laura F
LF
Nicolas
Emmanuelle
E
Hensley
Harvey
H
Jordan
V Craig
VC
Walker
Cheryl L
CL
Henske
Elizabeth P
EP
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*
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