FP36-6 Uterine-specific Loss of Tsc2 Leads to Leiomyoma Development and Myometrial Lung Tumors with Lymphangioleiomyomatosis Features

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP36-Ovarian & Uterine Function
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:10 AM
Room 104 (Moscone Center)

Poster Board MON-583
Hen Prizant*1, Sungnam Cho2, Francesco J DeMayo3, John P Lydon3 and Stephen R Hammes1
1University of Rochester, Rochester, NY, 2Baylor College of Medicine, Huston, TX, 3Baylor College of Medicine, Houston, TX
Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of abnormal smooth-muscle cells mainly in the lungs, leading to progressive functional loss and sometimes lung transplantation. While the origin of the LAM cells is unknown, several features of LAM provide us with clues. First, LAM cells contain inactivating mutations in genes encoding Tsc1 or Tsc2, proteins that limit mTORC1 activity. Second, LAM tumors recur after lung transplantation, suggesting a metastatic pathogenesis. Third, LAM is found almost exclusively in women. Finally, LAM shares many features with uterine leiomyomas, benign tumors derived from myometrial cells. Based on these observations, we proposed that LAM cells might originate from uterine leiomyomas containing Tsc mutations. To test our hypothesis, and to develop a mouse model for leiomyoma and LAM, we targeted Tsc2 deletion in uterine cells. In fact, nearly 100% of uteri from uterine-specific Tsc2 knockout mice developed myometrial proliferation and uterine leiomyomas by 12 and 24 weeks, respectively. Myometrial proliferation was prevented by the mTORC1 inhibitor rapamycin or by elimination of sex steroid production through ovariectomy. In ovariectomized mice, myometrial growth was restored by estrogen but not progesterone. Thus, both estrogen and mTORC1 signaling appear necessary for myometrial proliferation. Finally, we found Tsc2 null myometrial tumors in the lungs of 31-week and older Tsc2 uterine-specific knockout females. These lung tumors express progesterone receptors, estrogen receptors, smooth-muscle-actin alpha, phosphorylated S6, and are negative for the lung marker, Nkx2.1, suggesting that lung LAM-like myometrial lesions may indeed originate from the uterus. This mouse model may improve our understanding of both LAM and leiomyomas, and might lead to the development of novel therapeutic strategies for both diseases.

Nothing to Disclose: HP, SC, FJD, JPL, SRH

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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