This proposal is focused on the molecular mechanisms underlying the pathogenesis of lymphangioleiomyomatosis (LAM), a devastating disease affecting young women. The reasons that LAM affects women almost exclusively are not yet clearly defined. We have discovered that estrogen promotes the survival and lung colonization of intravenously injected Tsc2-null ELT3 cells. Our central hypothesis is that estrogen promotes the survival of tuberin-deficient cells, thereby allowing LAM cells to accumulate in the lungs and lymphatics. To address this hypothesis, we propose three Specific Aims:
Aim 1. To identify the molecular mechanisms through which estrogen enhances the survival and metastasis of tuberin-deficient cells. We will test the hypothesis that Bim (Bcl-2 interacting mediator of cell death) is a mediator of estrogen-promoted survival and identify the signaling events that underlie the enhanced levels of Bim in estrogen-treated ELT3 cells.
Aim 2. To determine whether estrogen enhances the survival of LAM-derived cells in vitro and in vivo. We will determine whether E2 promotes the survival of LAM-derived cells in vitro in either detached or attached conditions using a novel approach to distinguish between LAM cells and stromal cells, and determine whether E2 enhances the survival and/or metastasis of LAM-derived cells in vivo.
Aim 3. To determine whether inhibition of MEK1/2 and ER( leads to a regression of established lung metastasis of ELT3 cells. We will determine whether targeting MEK1/2 or ER( prevents further progression or induces regression of E2-induced lung metastasis of ELT3 cells. We will identify additional molecular determinants of E2-dependent survival of ELT3 cells using a modern proteomic approach.

Public Health Relevance

Our long-term goal is to identify the molecular mechanisms that underlie the female predominance of LAM, and thereby facilitate the development of effective therapeutic approaches for the treatment of LAM.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Peavy, Hannah H
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Brigham and Women's Hospital
United States
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Sun, Yang; Zhang, Erik; Lao, Taotao et al. (2014) Progesterone and estradiol synergistically promote the lung metastasis of tuberin-deficient cells in a preclinical model of lymphangioleiomyomatosis. Horm Cancer 5:284-98
Alayev, Anya; Sun, Yang; Snyder, Rose B et al. (2014) Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells. Cell Cycle 13:371-82
Li, Chenggang; Lee, Po-Shun; Sun, Yang et al. (2014) Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J Exp Med 211:15-28
Li, Chenggang; Zhang, Erik; Sun, Yang et al. (2014) Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis. PLoS One 9:e104809
Sun, Y; Gu, X; Zhang, E et al. (2014) Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells. Cell Death Dis 5:e1231
Gu, Xiaoxiao; Yu, Jane J; Ilter, Didem et al. (2013) Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis. Proc Natl Acad Sci U S A 110:14960-5
Csibi, Alfred; Fendt, Sarah-Maria; Li, Chenggang et al. (2013) The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153:840-54
Li, Chenggang; Zhou, Xiaobo; Sun, Yang et al. (2013) Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 49:135-42
Parkhitko, Andrey; Myachina, Faina; Morrison, Tasha A et al. (2011) Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A 108:12455-60