Estrogen-independent activation of erbBs signaling and estrogen receptor α in the mouse vagina exposed neonatally to diethylstilbestrol

Miyagawa, Shinichi; Katsu, Yoshinao; Watanabe, Hidenobu; Iguchi, Taisen

doi:10.1038/sj.onc.1207207

Cited by 43 publications

(54 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have analyzed the factors involved in vaginal cell proliferation and differentiation focusing on growth factors and cytokines (Miyagawa et al 2004). The novel finding in the present study is that genes related to the IL-1 system (IL-1L1 and IL-1 RII) were increased in expression in the neoDES vagina.…”

Section: Microarray Analysis Of Gene Expression Changes In the Neodesmentioning

confidence: 56%

“…For example, in the vagina, neonatal estrogen administration induces persistent cell proliferation and cornification of vaginal epithelium even after ovariectomy (OVX), resulting in hyperplastic lesions later in life (Takasugi et al 1962, Forsberg 1979, McLachlan et al 1980. We previously reported that persistent erbB receptor phosphorylation and sustained expression of epidermal growth factor-like growth factors contributed to persistent action in the neonatally DES-exposed vagina (Miyagawa et al 2004). However, the underlying mechanisms remain unknown, therefore, additional factors must be present.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol

Miyagawa¹,

Suzuki²,

Katsu³

et al. 2004

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Developmental exposure to a synthetic estrogen, diethylstilbestrol (DES), induces carcinogenesis in human and laboratory animals. In mice, neonatal DES treatment induces persistent proliferation and keratinization of the vaginal epithelium, even in the absence of the ovaries, resulting in cancerous lesions later in life. To understand the mechanisms underlying this persistent cell proliferation and differentiation, we characterized the gene expression patterns in the neonatally DES-exposed mouse vagina using DNA microarray and real-time quantitative RT-PCR. We found that genes related to cellular signaling, which are candidates for mediating the persistent proliferation and differentiation, were altered, and genes related to the immune system were decreased in the neonatally DES-exposed mouse vagina. We also noted high expression of interleukin-1 (IL-1)-related genes accompanied by phosphorylation of JNK1. In addition, expression IGF-I and its binding proteins was modulated and led to phosphorylation of IGF-I receptor and Akt, which is one of the downstream factors of IGF-I signaling. This led us to characterize the expression as well as the phosphorylation status of IL-1 and IGF-I signaling pathway components which may activate the phosphorylation cascade in the vagina of mice exposed neonatally to DES. These findings give insight into persistent activation in the vagina of mice exposed neonatally to DES.

show abstract

Section: Microarray Analysis Of Gene Expression Changes In the Neodesmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol

Miyagawa¹,

Suzuki²,

Katsu³

et al. 2004

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…ErbB signaling has long been implicated downstream of steroid hormone signaling in female reproductive organs (8,9,33). In the current study, we found that the erbB ligand, AREG, is expressed specifically in the epithelium, dependent on epithelial ESR1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Total RNA (2 μg), isolated from each group using an RNeasy kit (Qiagen), was used in RT-PCR reactions carried out with SuperScript III reverse transcriptase and SYBR Green Master Mix (Life Technologies), according to manufacturer's instructions. PCR conditions and sequences of some primer sets are given in a previous report (33). Others used are Pgr, TAT GAG AAC CCT TGA CGG TGT TG, CAG GGC CTG GCT CTC GTT A; Cebpb, CGG GTT TCG GGA CTT GAT GCA AT, CTA GAC AGT TAC ACG TGT GTT GCG.…”

Section: Methodsmentioning

confidence: 99%

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

Miyagawa

Iguchi

2015

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…EGFR-targeted therapy has been validated in human colorectal cancer (14), and the chemotherapeutics include pharmacological agents, including cetuximab (Erbitux), which is an EGFR inhibitor (15). EGFR acts to bind an EGFR-selective ligand activated by epidermal growth factor (EGF), transforming growth factor-α, amphiregulin or neuregulin, finally leading to cell proliferation, invasion and the inhibition of apoptosis (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells

Horng

Yang

Chiang³

et al. 2015

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract.Tetrandrine has been shown to reduce cancer cell proliferation and to inhibit metastatic effects in multiple cancer models in vitro and in vivo. However, the effects of tetrandrine on the underlying mechanism of HT29 human colorectal adenocarcinoma cell metastasis remain to be fully elucidated. The aim of the present study was focused on tetrandrine-treated HT29 cells following epidermal growth factor (EGF) treatment, and Transwell, gelatin zymography, gene expression and immunoblotting assays were performed to investigate metastatic effects in vitro. Tetrandrine was observed to dose-dependently inhibit EGF-induced HT29 cell invasion and migration, however, no effect on cell viability occurred following exposure to tetradrine between 0.5 and 2 µM. Tetrandrine treatment inhibited the enzymatic activity of matrix metalloprotease (MMP)-2 and MMP-9 in a concentration-dependent manner. The present study also found a reduction in the mRNA expression levels of MMP-2 and MMP-9 in the tetrandrine-treated HT29 cells. Tetrandrine also suppressed the phosphorylation of EGF receptor (EGFR) and its downstream pathway, including phosphoinositide-dependent kinase 1, phosphatidylinositol 3-kinase and phosphorylated AKT, suppressing the gene expression of MMP-2 and MMP-9. Furthermore, tetrandrine triggered mitogen-activated protein kinase signaling through the suppressing the activation of phosphorylated extracellular signal-regulated protein kinase. These data suggested that targeting EGFR signaling and its downstream molecules contributed to the inhibition of EGF-induced HT29 cell metastasis caused by tetrandrine, eventually leading to a reduction in the mRNA and gelatinase activities of MMP-2 and MMP-9, respectively. IntroductionEpidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases (1), and EGFR activation by ligand binding stimulates multiple signals, including phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinases (MAPKs) and nuclear factor-κB pathways, ultimately resulting in cellular proliferation, survival, angiogenesis invasion and metastasis (2,3). Abnormal protein activity and/or expression levels of EGFR have been correlated with the etiology of several types of human cancer, including colorectal cancer (4,5), non-small cell lung cancer (6,7), breast cancer (8,9), head and neck squamous cell carcinoma (10,11), pancreatic cancer (12) and brain cancer (13). EGFR-targeted therapy has been validated in human colorectal cancer (14), and the chemotherapeutics include pharmacological agents, including cetuximab (Erbitux), which is an EGFR inhibitor (15). EGFR acts to bind an EGFR-selective ligand activated by epidermal growth factor (EGF), transforming growth factor-α, amphiregulin or neuregulin, finally leading to cell proliferation, invasion and the inhibition of apoptosis (15)(16)(17).Tetrandrine is a bisbenzylisoquinoline alkaloid, which is isolated from the dried root of Stephania tetrandra of the

show abstract

Estrogen-independent activation of erbBs signaling and estrogen receptor α in the mouse vagina exposed neonatally to diethylstilbestrol

Cited by 43 publications

References 44 publications

Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol

Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol

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

Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells

Contact Info

Product

Resources

About