Uterine leiomyoma in the Eker rat: A unique model for important diseases of women

Walker, Cheryl L.; Hunter, Deborah; Everitt, Jeffrey I.

doi:10.1002/gcc.10281

Cited by 82 publications

(75 citation statements)

References 67 publications

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“…Uterine leiomyoma development in Eker rats is similarly hormonedependent. Ovariectomy virtually ablates tumor development in this model, and leiomyoma-derived cells display an estrogenresponsive phenotype (23).…”

mentioning

confidence: 85%

“…To determine the mechanism by which developmental DES exposure enhanced tumor-suppressor-gene penetrance, we examined developmental programming of the target tissue as a candidate mechanism for modulation of tumor outcome in genetically susceptible animals. Uterine leiomyomas are hormone-dependent, and tumor development in the Eker rat requires the steroid hormone estrogen (23). To determine whether developmental programming had occurred in the target tissue before tumor development, we examined the myometria of female rats for expression of the PR and AR, two well characterized estrogen-responsive genes.…”

Section: Developmental Programming Enhances the Estrogen-responsivenessmentioning

confidence: 99%

“…In women, tumor-suppressor genes such as BRCA1͞2 and PTEN are known to increase the risk for hormone-dependent tumors of the breast and female reproductive tract, but the availability of mouse models in which these or other specific tumor-suppressor-gene defects result in the development of spontaneous hormone-dependent tumors of the female reproductive tract is limited (5,20). However, Eker rats carrying a germ-line defect in one allele of the Tsc-2 tumor-suppressor gene are a well characterized model for hormone-dependent tumors of the female reproductive tract (21)(22)(23). Tsc-2 functions as an important regulator of phosphatidylinositol 3-kinase signaling downstream from AKT, serving to negatively regulate mTOR (24).…”

mentioning

confidence: 99%

“…Tsc-2 participates in tumor formation by the classic ''two-hit'' mechanism proposed by Knudson (28), with loss of function of tuberin observed in human, rat, and mouse TSC-2-associated lesions. Female rats carrying the Eker mutation (Tsc-2 Ek/ϩ ) spontaneously develop uterine leiomyomas with a penetrance of 65% by 16 mo of age (23). In women, uterine leiomyoma is an ovarian hormone-dependent tumor that is the most common tumor of the reproductive tract and the major cause of hysterectomy in women of reproductive age.…”

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confidence: 99%

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Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

Cook

Davis

Cai

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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102

101

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Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumorsuppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an earlylife exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to >90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals.developmental programming ͉ gene-environment interaction ͉ Eker rat ͉ uterine leiomyoma ͉ Tsc-2 I nheritance of a defect in a tumor-suppressor gene confers a high risk for developing cancer. However, defects in these genes are rarely 100% penetrant, and, even in families harboring the same genetic mutation, the penetrance of the tumor-suppressor-gene defect can vary significantly (1-4). The importance of geneenvironment interactions in contributing to individual differences in tumor-suppressor-gene penetrance was recently highlighted in the New York Breast Cancer Study, which evaluated the breast and ovarian cancer risk in female relatives harboring mutations in the BRCA1 and BRCA2 tumor-suppressor genes. The magnitude of increase in breast cancer risk in the birth cohort born after 1940 was substantially greater than in those born before 1940 (5). These data suggest that additional factors, such as diet, exercise, hormonal milieu, and environmental exposures, can significantly modify cancer risk in the presence of an inherited cancer-susceptibility gene.Traditionally, gene-environment interactions that influence cancer risk are thought to occur over an individual's lifetime by facilitating or inhibiting acquisition of the multiple somatic mutations required for tumorigenesis (6). However, for some diseases, such as cardiovascular disease and adult-onset diabetes, a developmental programming hypothesis is proposed as an alternative mechanism for modulating adult disease. This hypo...

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mentioning

confidence: 85%

Section: Developmental Programming Enhances the Estrogen-responsivenessmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

Cook

Davis

Cai

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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102

101

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“…These lines, isolated from uterine leiomyomas, exhibit expression of smooth muscle antigens and constitutive activation of mTOR kinase. All of these cell lines express receptors for estrogen and progesterone, however, only ELT6 was shown to respond to these hormones in culture [44]. Although TSC1 and TSC2 knockouts are lethal, a cell line derived from embryonic TSC2-null Eker rat, named EEF-8, was obtained, as well as TSC2 -/-fibroblasts derived from this model [45].…”

Section: Cell Lines As a Model Of Lammentioning

confidence: 99%

LAM cells biology and lymphangioleiomyomatosis

Grzegorek¹,

Drożdż²,

Podhorska-Okołów³

et al. 2013

Folia Histochem Cytobiol.

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Abstract:Progressive lung tissue destruction in lymphangioleiomyomatosis (LAM) occurs as a result of excessive proliferation of LAM cells caused by a mutation in one of the tuberous sclerosis complex suppressor genes, TSC1 or TSC2. These cells show constitutive activation of the mammalian target of rapamycin (mTOR) pathway and many of the mTOR-related kinases such as Akt, Erk, S6K1 and S6. Phenotype of LAM cells differs considerably depending on their microenvironment. LAM cells show differences in morphology, size and expression of various factors depending on their location in the tumor or body fluids. The presence of LAM cells in blood, urine, bronchoalveolar lavage fluid (BALF), and chyle proves their ability to metastasis. Antigens of smooth muscle cells are expressed in most LAM cells. Some of these cells are immunoreactive with HMB-45 antibody, which is used for the immunohistochemical diagnosis of LAM. Receptors for estrogen and progesterone may also be expressed in these cells, which probably is associated with the fact that LAM occurs almost exclusively in women of childbearing age. LAM cells via increased production of metalloproteinases are involved in the destruction of the extracellular matrix, as well as the remodeling and damage of lung tissue. Sporadic LAM occurs extremely rarely. Therefore a good experimental model of this disease is necessary. To date, several animal and human cell lines, which both genetically and phenotypically resemble LAM cells, have been obtained. These cell lines, derived from LAM nodule or an angiomyolipoma, are usually characterized by a mutation of the TSC2 gene, expression of smooth muscle cell antigens such as a-smooth muscle actin (aSMA) or S6K1 and S6 protein hyperphosphorylation. Presently, there is no commercially available cell line representing a good model of LAM. A better understanding of LAM cell biology is necessary for creating a useful model in vitro for further exploration of both LAM pathomechanisms and more general mechanisms of carcinogenesis. (Folia Histochemica et Cytobiologica 2013, Vol. 51, No. 1, 1-10) Abbreviations 4E-BP1 -eukaryotic translation initiation factor 4E-binding protein 1; AKT -protein kinase B; BALF -bronchoalveolar lavage fluid; EGF -epidermal growth factor; EGFR -epidermal growth factor receptor; elF4E -eukaryotic initiation factor-like protein; EMMPRIN -extracellular matrix metalloproteinase inducer; ER -estrogen receptor; ERKextracellular signal-regulated kinase; HIF-1a a a a a -hypoxia-inducible factor 1a; IGF-1 -insulin-like growth factor 1; LAM -lymphangioleiomyomatosis; LOH -loss of heterozygosity; MAPK -mitogen-activated protein kinase; MART-1 -melanoma-associated antigen recognized by T cells; MEFs -mouse embryo fibroblasts; MMPs -matrix metalloproteinases; mTOR -mammalian target of rapamycin; PAI-1 -plasminogen activation inhibitor; PDK1 -phosphoinositide-dependent kinase-1; PGE2 -endogenous prostaglandin E2; PgR -progesterone receptor; PI3K -phosphoinositide 3-kinase; PLG -plasminogen; Rheb -Ras homolog enriched in ...

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Rat and Mouse Models of Tuberous Sclerosis

Kwiatkowski

2010

Tuberous Sclerosis Complex

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Uterine leiomyoma in the Eker rat: A unique model for important diseases of women

Cited by 82 publications

References 67 publications

Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

LAM cells biology and lymphangioleiomyomatosis

Rat and Mouse Models of Tuberous Sclerosis

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