A HOXA10 Estrogen Response Element (ERE) is Differentially Regulated by 17 Beta-estradiol and Diethylstilbestrol (DES)

Akbas, G. Eda; Song, J. J.; Taylor, Hugh S.

doi:10.1016/j.jmb.2004.05.052

Cited by 87 publications

(82 citation statements)

References 50 publications

(43 reference statements)

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“…[31][32][33] In this study, we observed consistent and significant down-regulation of Hoxa11 in DES-promoted endometrial cancers. As predicted from the expression pattern of Hoxa11 in tight cluster 5 (Fig.…”

Section: Resultssupporting

confidence: 76%

Transcriptional profiling endometrial carcinomas microdissected from DES‐treated mice identifies changes in gene expression associated with estrogenic tumor promotion

Kabbarah

Mallon

Pfeifer

et al. 2006

Intl Journal of Cancer

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Exposure to unopposed estrogen is a potent risk factor for developing human endometrial cancer. However, little is known about the transcriptional changes elicited by estrogens in endometrial carcinogenesis, in part, because of genetic and environmental heterogeneity of human tumors. We have begun to chart the expression signatures of endometrial tumors promoted with the synthetic estrogen, diethylstilbestrol (DES), in inbred mice. As expected, laser-capturemicrodissected endometrial cancers from DES-treated mice displayed a large number of transcriptional changes when compared to uninvolved endometrial epithelium. Genes differentially expressed in carcinomas included cell adhesion and extracellular matrix genes (Decorin as 1 example), developmental genes (Hoxa11), and cytokine signaling genes (Socs3). The DES-promoted carcinomas appeared to fall into 2 distinct transcriptional classes, and expression of the tumor suppressor Pten was among the top discriminators between the 2 cancer groups. Pten was down regulated in the majority of the DES-promoted carcinomas, which is analogous to the frequent loss of PTEN expression in human endometrial tumors. Although preliminary, these observations suggest that the cancers that arise in the DES model bear similarities to human endometrial cancers and provide insights into transcriptional alterations that accompany estrogen-driven endometrial carcinogenesis. ' 2006 Wiley-Liss, Inc.Key words: DES; gene expression profiling; endometrial carcinoma; mouse model Cancer represents the phenotypic end-point of an evolutionary process that is driven by interactions between genes and the cellular environment. Molecular and epidemiological studies have highlighted key genetic factors in human endometrial tumorigenesis, including loss or epigenetic silencing of the tumor suppressor gene phosphatase and tensin homologue (PTEN) 1 and the DNA mismatch repair (MMR) genes mutL homologue 1 (MLH1), mutS homologue 2 (MSH2) and mutS homologue 6 (MSH6). [2][3][4][5] It is widely accepted that exposure to unopposed estrogen (estrogen in the absence of progesterone) is a potent environmental risk factor for the development of a variety of malignancies, and in particular endometrial carcinoma. 6-8 However, deciphering the genes and pathways that are disturbed in estrogen-promoted endometrial cancers has been a difficult task, due in part to the inherent genetic and hormonal heterogeneity that characterizes this tumor type.Mouse models for endometrial tumorigenesis have been developed using estrogenic compounds, such as 17b-estradiol, tamoxifen and diethylstilbestrol (DES). 9,10 The synthetic estrogen, DES, is a compound of great clinical relevance. It was administered to more than six million women between the 1940s and the early 1970s, and in utero exposure to this compound was later linked to malformation in the female reproductive tract 11,12 and to clear-cell adenocarcinoma of the vagina and cervix. 13,14 The cancer phenotypes associated with DES exposure in humans and mice are clearly differe...

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Section: Resultssupporting

confidence: 76%

Transcriptional profiling endometrial carcinomas microdissected from DES‐treated mice identifies changes in gene expression associated with estrogenic tumor promotion

Kabbarah

Mallon

Pfeifer

et al. 2006

Intl Journal of Cancer

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“…Diethylstilbestrol (DES) is a nonsteroidal estrogen, a well-known teratogen. This chemical alters the localization of Hox gene expression along the axis of the developing murine reproductive tract, and induces developmental anomalies of female reproductive tract (Ma et al 1998;Akbas et al 2004). DES exposure in utero shifts Hoxa9 expression from the oviducts to the uterus and leads to decreases in both Hoxa10 and Hoxa11 expression in the uterus.…”

Section: Estrogens and Progesterone Regulate Hox Gene Expression In Tmentioning

confidence: 99%

The Role ofHoxGenes in Female Reproductive Tract Development, Adult Function, and Fertility

Taylor

2015

Cold Spring Harb Perspect Med

196

158

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HOX genes convey positional identity that leads to the proper partitioning and adult identity of the female reproductive track. Abnormalities in reproductive tract development can be caused by HOX gene mutations or altered HOX gene expression. Diethylstilbestrol (DES) and other endocrine disruptors cause Mü llerian defects by changing HOX gene expression. HOX genes are also essential regulators of adult endometrial development. Regulated HOXA10 and HOXA11 expression is necessary for endometrial receptivity; decreased HOXA10 or HOXA11 expression leads to decreased implantation rates. Alternation of HOXA10 and HOXA11 expression has been identified as a mechanism of the decreased implantation associated with endometriosis, polycystic ovarian syndrome, leiomyoma, polyps, adenomyosis, and hydrosalpinx. Alteration of HOX gene expression causes both uterine developmental abnormalities and impaired adult endometrial development that prevent implantation and lead to female infertility.

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“…Generally, recruitment of specific DNA-binding proteins to the promoter sequence is essential for transcriptional initiation. A variety of regulatory elements, including general and tissue-specific regulatory elements, have been identified in several Hox genes: Hoxb3 (Kwan et al, 2001), Hoxb4 (Gutman et al, 1994), Hoxa5 (Nowling et al, 1999), Hoxa7 (Puschel et al, 1991;Knittel et al, 1995), Hoxa9 (Yan et al, 2006a) and Hoxa10 (Akbas et al, 2004). These regulatory elements are much conserved among cluster genes and even among interspecies of Hox genes from human and mouse (Knittel et al, 1995;Kwan et al, 2001;Lehoczky et al, 2004).…”

Section: Initiation Of Hox Expressionmentioning

confidence: 99%

Epigenetic regulations in hematopoietic Hox code

Hua

Yan

2010

Oncogene

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A HOXA10 Estrogen Response Element (ERE) is Differentially Regulated by 17 Beta-estradiol and Diethylstilbestrol (DES)

Cited by 87 publications

References 50 publications

Transcriptional profiling endometrial carcinomas microdissected from DES‐treated mice identifies changes in gene expression associated with estrogenic tumor promotion

Transcriptional profiling endometrial carcinomas microdissected from DES‐treated mice identifies changes in gene expression associated with estrogenic tumor promotion

The Role ofHoxGenes in Female Reproductive Tract Development, Adult Function, and Fertility

Epigenetic regulations in hematopoietic Hox code

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