Expression of a dominant negative estrogen receptor alpha variant in transgenic mice accelerates uterine cancer induced by the potent estrogen diethylstilbestrol

Davis, Vicki L.; Newbold, Retha R.; Couse, John F.; Rea, Sheri L.; Gallagher, Katie M.; Hamilton, Katherine; Goulding, Eugenia H.; Jefferson, Wendy N.; Eddy, Edward M.; Bullock, Bill C.; Korach, Kenneth S.

doi:10.1016/j.reprotox.2012.08.005

Cited by 12 publications

(6 citation statements)

References 61 publications

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“…After NP and ER forming a ligand, they bind the response element in DNA binding domain and then induce or inhibit transcription of target genes, starting a series of estrogen-dependent physiological and biochemical processes [47]. ER has two subtypes: ER-α and ER-β; both can be expressed at different levels in normal liver tissue [48]. NP altered the expression of ER-α and ER-β in NCTC Clone 1469.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress and Apoptosis Contributed to Nonylphenol-Induced Cell Damage in Mouse NCTC Clone 1469 Cells

Liu

Chen

Nie

et al. 2020

Journal of Chemistry

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Nonylphenol (NP) is considered an environmental toxicant and endocrine-disrupting compound. The present study aimed to investigate the effects of NP on NCTC Clone 1469, nonparenchymal hepatocytes, and to study the molecular basis of NP-induced liver injury. The results showed that NP decreased cell viability and induced nucleus crenulation and intracellular enzyme leakage in NCTC Clone 1469 cells. Additionally, NP-induced oxidative stress and apoptosis of NCTC Clone 1469 are accompanied by upregulating reactive oxygen species (ROS) production, increase of Bax, decrease of Bcl-2, activation of caspase-3 and caspase-12, and release of cytosolic free Ca2+ in the cells. ROS scavenger, N-acetyl-L-cysteine (NAC), prevented the intracellular enzyme leakage induced by NP. NP induced alteration of estrogen receptor- (ER-) α and ER-β expression, while ER antagonists, ICI 182,780, showed no effect on NP-induced intracellular enzyme leakage. We proposed that NP triggered cell damage via inducing oxidative stress and apoptosis in cells, but not estrogenic effect.

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Section: Discussionmentioning

confidence: 99%

Oxidative Stress and Apoptosis Contributed to Nonylphenol-Induced Cell Damage in Mouse NCTC Clone 1469 Cells

Liu

Chen

Nie

et al. 2020

Journal of Chemistry

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“…Higher circulating 17β-estradiol levels and non-classical signaling may be related to the earlier incidence of uterine cancer in transgenic mice. These findings indicate that expression of the ERα variant can influence determining events in uterine cancer development and its natural occurrence in the human uterus would unlikely be protective [71].…”

Section: Journal Of Clinical Epigenetics Issn 2472-1158mentioning

confidence: 96%

Adverse Effects on Female Human Reproductive Health from Exposure to Endocrine Disruptors: Focus on Endometrial Lesions

Karoutsou¹,

Karoutsos²,

Karoutsos³

2016

J Clin Epigenet

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It is currently apparent that the intentional release of compounds through agricultural, industrial, and municipal activities has influenced the health of wildlife and human populations. Scientists are invited to study disturbances in the normal function of the reproductive system of genetically modified populations. When referring to a population, they rather use the term control or reference; the reason is an enormous rate of information concerning the endocrine-altering potential of plasticizers and dyes, as well as the possible influences of pesticides and industrial compounds on various endocrine endpoints, particularly regarding the concentration of estrogens. Here in, we provide an overview on the impact of chemical substances on female human reproductive health.

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“…DES (1 mg/kg/day) on PND1-5 is an established dose with high efficacy ($90% uterine cancer), which we used to reduce variability in our endpoints to understand the molecular mechanisms underlying endometrial carcinogenesis. Sample sizes were calculated on the basis of previously published studies showing that 45% of FVB/N mice exposed neonatally to DES develop cancer by 8 months of age (31,32). We estimated that using 12 mice per exposure group and genotype would allow us to detect a 45% difference in cancer incidence (one-sided 0.05 level of significance with 80% power) beginning at 6 months.…”

Section: Animalsmentioning

confidence: 99%

SIX1 Regulates Aberrant Endometrial Epithelial Cell Differentiation and Cancer Latency Following Developmental Estrogenic Chemical Exposure

Suen

Jefferson

Wood

et al. 2019

Molecular Cancer Research

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Early-life exposure to estrogenic chemicals can increase cancer risk, likely by disrupting normal patterns of cellular differentiation. Female mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) develop metaplastic and neoplastic uterine changes as adults. Abnormal endometrial glands express the oncofetal protein sine oculis homeobox 1 (SIX1) and contain cells with basal [cytokeratin (CK) 14 þ /18 À ] and poorly differentiated features (CK14 þ /18 þ ), strongly associating SIX1 with aberrant differentiation and cancer. Here, we tested whether SIX1 expression is necessary for abnormal endometrial differentiation and DES-induced carcinogenesis by using Pgr-cre to generate conditional knockout mice lacking uterine Six1 (Six1 d/d ). Interestingly, corn oil (CO) vehicle-treated Six1 d/d mice develop focal endometrial glandular dysplasia and features of carcinoma in situ as compared with CO wild-type Six1 (Six1 þ/þ ) mice. Furthermore, Six1 d/d mice neonatally exposed to DES had a 42% higher incidence of endometrial cancer relative to DES Six1 þ/þ mice.Although DES Six1 d/d mice had >10-fold fewer CK14 þ /18 À basal cells within the uterine horns as compared with DES Six1 þ/þ mice, the appearance of CK14 þ /18 þ cells remained a feature of neoplastic lesions. These findings suggest that SIX1 is required for normal endometrial epithelial differentiation, CK14 þ /18 þ cells act as a cancer progenitor population, and SIX1 delays DES-induced endometrial carcinogenesis by promoting basal differentiation of CK14 þ /18 þ cells. In human endometrial biopsies, 35% of malignancies showed CK14 þ / 18 þ expression, which positively correlated with tumor stage and grade and was not present in normal endometrium.Implications: Aberrant epithelial differentiation is a key feature in both the DES mouse model of endometrial cancer and human endometrial cancer. The association of CK14 þ /18 þ cells with human endometrial cancer provides a novel cancer biomarker and could lead to new therapeutic strategies.

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Expression of a dominant negative estrogen receptor alpha variant in transgenic mice accelerates uterine cancer induced by the potent estrogen diethylstilbestrol

Cited by 12 publications

References 61 publications

Oxidative Stress and Apoptosis Contributed to Nonylphenol-Induced Cell Damage in Mouse NCTC Clone 1469 Cells

Oxidative Stress and Apoptosis Contributed to Nonylphenol-Induced Cell Damage in Mouse NCTC Clone 1469 Cells

Adverse Effects on Female Human Reproductive Health from Exposure to Endocrine Disruptors: Focus on Endometrial Lesions

SIX1 Regulates Aberrant Endometrial Epithelial Cell Differentiation and Cancer Latency Following Developmental Estrogenic Chemical Exposure

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