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.

DOI: 10.1073/pnas.0810790106
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@article{Yu2009EstrogenPT, title={Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells.}, author={Jane J Yu and Victoria A Robb and Tasha A Morrison and Eric A Ariazi and Magdalena Karbowniczek and Aristotelis Astrinidis and Chunrong Wang and Lisa Hernandez-Cuebas and Laura F Seeholzer and Emmanuelle Nicolas and Harvey Hensley and V Craig Jordan and Cheryl L Walker and Elizabeth P Henske}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2009}, volume={106 8}, pages={2635-40} }