TY - JOUR
T1 - Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells
AU - Yu, Jane J.
AU - Robb, Victoria A.
AU - Morrison, Tasha A.
AU - Ariazi, Eric A.
AU - Karbowniczek, Magdalena
AU - Astrinidis, Aristotelis
AU - Wang, Chunrong
AU - Hernandez-Cuebas, Lisa
AU - Seeholzer, Laura F.
AU - Nicolas, Emmanuelle
AU - Hensley, Harvey
AU - Jordan, V. Craig
AU - Walker, Cheryl L.
AU - Henske, Elizabeth P.
PY - 2009/2/24
Y1 - 2009/2/24
N2 - 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-β-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 MARK 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.
AB - 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-β-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 MARK 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.
KW - Anoikis
KW - Bim
KW - Lymphangioleiomyomatosis
KW - MAPK
KW - Rheb
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UR - http://www.scopus.com/inward/citedby.url?scp=62449318120&partnerID=8YFLogxK
U2 - 10.1073/pnas.0810790106
DO - 10.1073/pnas.0810790106
M3 - Article
C2 - 19202070
AN - SCOPUS:62449318120
SN - 0027-8424
VL - 106
SP - 2635
EP - 2640
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 8
ER -