Uterine-Specific Loss of Tsc2 Leads to Myometrial Tumors in Both the Uterus and Lungs

Abstract

Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of abnormal smooth-muscle cells in the lungs, leading to functional loss and sometimes lung transplantation. Although the origin of LAM cells is unknown, several features of LAM provide 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 features with uterine leiomyomas, benign tumors of myometrial cells. From these observations, we proposed that LAM cells might originate from uterine leiomyomas containing Tsc mutations. To test our hypothesis, and to develop mouse models for leiomyoma and LAM, we targeted Tsc2 deletion primarily 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 and mTORC1/S6 activity were abrogated by the mTORC1 inhibitor rapamycin or by elimination of sex steroid production through ovariectomy or aromatase inhibition. In ovariectomized Tsc2 null mice, mTORC1/S6 activity and myometrial growth were restored by estrogen but not progesterone. Thus, even without Tsc2, estrogen appears to be required for myometrial mTORC1/S6 signaling and proliferation. Finally, we found Tsc2 null myometrial tumors in lungs of older Tsc2 uterine-specific knockout females, suggesting that lung LAM-like myometrial lesions may indeed originate from the uterus. This mouse model may improve our understanding of LAM and leiomyomas and might lead to novel therapeutic strategies for both diseases.

Progesterone and Estradiol Synergistically Promote the Lung Metastasis of Tuberin-Deficient Cells in a Preclinical Model of Lymphangioleiomyomatosis

“…Recently, Gao et al have reported that the expression of progesterone receptor is significantly higher than that of estrogen receptor in pulmonary LAM, suggesting a potential role of PgR in LAM pathogenesis [47]. In a preclinical model of LAM, Prizant et al reported that E 2 or E 2 plus Pg increase the growth of uterine tumors and lung metastasis of uterine tumor cells, although Pg alone did not affect these alterations [24], consistent with our preclinical findings. Despite the lack of effect of Pg in lung metastasis of tumor cells, we observed striking alveolar alterations of immune cell infiltration and alveolar thickening in the lungs of mice treated with Pg.…”

“…Although the impact of estradiol on the growth and metastatic behaviors of TSC2-deficient cells have been reported, the influence of progesterone in these cellular outcomes has not been extensively investigated in the context of TSC2 deficiency and LAM. Recently, Prizant et al developed a novel uterine-specific Tsc2 knockout mouse model in which estradiol or estradiol plus progesterone promotes the growth of myometrial tumors and lung metastasis, although progesterone alone had no effect on these phenotypes [24]. In current study, we found that progesterone was sufficient to activate ERK1/2 and Akt signaling pathways, although not sufficient to promote tumor growth or lung metastasis of Tsc2-deficient cells, indicating a potentially key pathogenic mechanism of progesterone action underlying the female hormone-driven progression of LAM.…”

“…In preclinical models of LAM, estradiol promoted the survival and metastasis of TSC2-deficient cells [22–24]. Faslodex, a pure estradiol receptor antagonist, blocked estradiol-induced lung metastasis of Tsc2-deficient cells in a metastatic model [25].…”

“…Furthermore, in a recently developed uterine-specific Tsc2 knockout mouse model, estradiol treatment increased myometrial proliferation, which was suppressed by ovariectomy and aromatase inhibition. Interestingly, progesterone treatment did not affect the proliferation of myometrial [24]. Despite these findings, the impact of progesterone on the proliferation, survival, and metastasis of cells lacking TSC2 has not been extensively investigated.…”

Med12 gain-of-function mutation causes leiomyomas and genomic instability

“…There are 3 published Tg mouse models of uterine leiomyomas; these include Tg overexpression of hGPR10 driven with the calbindin-D9K promoter (16), conditional deletion of Tsc2 (17), and conditional expression of a gain-of-function mutant form of β-catenin (18). The phenotype in these mice is confined to increased myometrial thickness and formation of small nodules, but none of these mice show the dramatic tumors we report here (Figure 1).…”