Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells
Jane J Yu, Victoria A Robb, Tasha A Morrison, Eric A Ariazi, Magdalena Karbowniczek, Aristotelis Astrinidis, Chunrong Wang, Lisa Hernandez-Cuebas, Laura F Seeholzer, Emmanuelle Nicolas, Harvey Hensley, V Craig Jordan, Cheryl L Walker, Elizabeth P Henske, Jane J Yu, Victoria A Robb, Tasha A Morrison, Eric A Ariazi, Magdalena Karbowniczek, Aristotelis Astrinidis, Chunrong Wang, Lisa Hernandez-Cuebas, Laura F Seeholzer, Emmanuelle Nicolas, Harvey Hensley, V Craig Jordan, Cheryl L Walker, Elizabeth P Henske
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.
Conflict of interest statement
The authors declare no conflict of interest.
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Source: PubMed