β-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation

Villacorte, Mylah; Suzuki, Kentaro; Hirasawa, Akira; Ohkawa, Yasuyuki; Suyama, Mikita; Maruyama, Tetsuo; Aoki, Daisuke; Ogino, Yukiko; Miyagawa, Shinichi; Terabayashi, Takeshi; Tomooka, Yasuhiro; Nakagata, Naomi; Yamada, Gen

doi:10.1038/onc.2012.376

Cited by 46 publications

(43 citation statements)

References 42 publications

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“…These phenotypes were not a result of an insufficiency of E 2 exposure (see the following longterm E 2 exposure experiment). The K5-Esr1KO female mice are infertile, probably because of the expression of Cre recombinase in uterine epithelial cells (16).…”

Section: Resultsmentioning

confidence: 99%

Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina

Miyagawa

Iguchi

2015

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

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Estrogen-mediated actions in female reproductive organs are tightly regulated, mainly through estrogen receptor 1 (ESR1). The mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen and provides a unique model for analyzing the homeostasis of stratified squamous epithelia. To address the role of ESR1-mediated tissue events during homeostasis, we analyzed mice with a vaginal epitheliumspecific knockout of Esr1 driven by keratin 5-Cre (K5-Esr1KO). We show here that loss of epithelial ESR1 in the vagina resulted in aberrant epithelial cell proliferation in the suprabasal cell layers and led to failure of keratinized differentiation. Gene expression analysis showed that several known estrogen target genes, including erbB growth factor ligands, were not induced by estrogen in the K5-Esr1KO mouse vagina. Organ culture experiments revealed that the addition of erbB growth factor ligands, such as amphiregulin, could activate keratinized differentiation in the absence of epithelial ESR1. Thus, epithelial ESR1 integrates estrogen and growth factor signaling to mediate regulation of cell proliferation in squamous differentiation, and our results provide new insights into estrogen-mediated homeostasis in female reproductive organs.estrogen receptor | vagina | keratinization | amphiregulin | epithelium E strogens play important roles in vertebrate reproductive biology, with effects principally mediated through the nuclear estrogen receptors (ESRs). ESRs are members of the nuclear receptor superfamily and typically up-regulate gene transcription upon ligand binding. Two different genes encoding the two ESR subtypes, ESR1 (formerly named ERα) and ESR2 (formerly named ERβ), have been identified from a variety of vertebrate species. ESR1 is the predominant subtype regulating estrogen-mediated proliferation and differentiation of female reproductive organs. Administration of estrogens increases organ weights and promotes cell proliferation and differentiation, whereas such events were not evoked in the Esr1-deficient mice (1-3).Estrogen actions on the uterus and mammary gland have been extensively analyzed. During the first step of estrogen action, epithelial-stromal interactions play a pivotal role in epithelial cell proliferation. In vitro tissue recombination experiments with Esr1 knockout (KO)-and wild-type-derived epithelium and stroma revealed that the effects of estrogen on uterine and mammary epithelial cell proliferation are mediated primarily via stromally expressed ESR1 (4-6). Estrogen-induced growth factors secreted from the stroma subsequently promote epithelial cell proliferation (7-10). Experiments using epithelial cell-specific KO of Esr1 revealed that estrogen can induce proliferation of uterine epithelial cells despite the absence of epithelial ESR1 (11). In contrast, similar experiments using a mammary epithelium-specific Esr1 KO showed that ESR1 is required in the epithelial cells for mammary gland growth and ductal epithelial cell proliferation (12). It is u...

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Section: Resultsmentioning

confidence: 99%

Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina

Miyagawa

Iguchi

2015

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

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“…Thus, Lif gene activation by ligand-activated ESR1 is postulated to involve FOXA2 pioneer transcription activity (48,49). Future studies should focus on the molecular mechanism by which FOXA2 programs the GE transcriptome and influences steroid hormone responses of uterine glands, particularly because FOXA2 is expressed in the glands of the human uterus, is involved in endometrial hyperplasia (19), is frequently mutated and inactivated in endometrioid endometrial cancer (50), and is down-regulated in ectopic endometrium in women with endometriosis (51).…”

Section: On Gd 35 Induces the Expression Of Lif In The Glands Of Thementioning

confidence: 99%

“…Forkhead box transcription factors play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity in a number of different organs (16,17). FOXA2 is expressed specifically in the GE of the neonatal and adult uterus in mice (11,12,18) and also is expressed in the GE of the human uterus (19). Null mutation of Foxa2 is embryonic lethal in mice (20,21), because it is required for the development of endoderm-derived organs (17,22).…”

mentioning

confidence: 99%

Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Kelleher

Wang

Pru

et al. 2017

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

130

177

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Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy in mice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.T he uterus is comprised of two tissue compartments, the endometrium and the myometrium. The endometrium contains three cell types, luminal epithelium (LE), glandular epithelium (GE), and stroma. In mice, the uterus becomes receptive to blastocyst implantation on gestational day (GD) 4 (with the observation of a postcoital vaginal plug designated GD 0.5); it is prereceptive on GD 1-3, and by the afternoon of GD 5 it becomes nonreceptive (refractory) (1-3). Dynamic changes in ovarian estrogen and progesterone production act via the uterus to regulate uterine receptivity, blastocyst implantation, and stromal cell decidualization necessary for the establishment of pregnancy (4-6). The implantation process, which is initiated by the attachment of the blastocyst trophectoderm to the receptive LE, occurs before or right after midnight in the evening of GD 4 and becomes more prominent by the morning of GD 5. By GD 6, the trophectoderm begins to contact directly stromal cells that then begin to differentiate into decidual cells, which are required for successful pregnancy because they regulate placental development and local maternal immune responses (7,8).The infertility observed in leukemia inhibitory factor (Lif)-null mice and uterine gland-knockout (UGKO) mice and sheep established ...

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“…Conditional ablation and activation of B-catenin in the mouse uterine epithelia resulted in aberrant epithelial structures and endometrial hyperplasia formation respectively (Villacorte et al 2013). LEF1, a Wnt-pathway target gene, and its downstream targets cyclin D1 and MMP7 were found to have a role in endometrial gland formation and carcinogenesis (Shelton et al 2012).…”

Section: Cell Signaling Pathwaysmentioning

confidence: 99%

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Makker

Goel

2015

Endocrine-Related Cancer

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Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70-80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial-mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis -the most fatal consequence of endometrial carcinogenesis.

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β-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation

Cited by 46 publications

References 42 publications

Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina

Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina

Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

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