Estrogen signaling ability in human endometrial cancer through the cancer-stromal interaction

Matsumoto, Mitsuyo; Yamaguchi, Yuri; Seino, Yutaka; Hatakeyama, Atsushi; Takei, Hiroyuki; Niikura, Hitoshi; Itō, Kiyoshi; Suzuki, Takashi; Sasano, Hironobu; Yaegashi, Nobuo; Hayashi, Shin Ichi

doi:10.1677/erc-07-0227

Cited by 40 publications

(39 citation statements)

References 38 publications

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“…(15) We found the similar result that while GFP levels varied among cases, stromal fibroblasts could activate ER in the presence of testosterone, which was inhibited by aromatase inhibitors. These results suggest that aromatase inhibitor might be useful for hormonal therapy in endometrial cancers.…”

Section: Estrogen Signaling In the Cancer Microenvironmentsupporting

confidence: 69%

“…The amplified adenovirus infected cells prepared from tissue specimens by collagenase treatment. (15) The other assay system involves a reporter cell line which stably introduced the ERE-GFP reporter gene. We established a reporter cell line, named MCF-7-E10, to visualize ER activity stimulated by extracellular signals such as estrogen or other factors.…”

Section: Imaging Of Transcription Activity Of Nuclear Receptormentioning

confidence: 99%

“…(15) Furthermore, anti-estrogen or aromatase inhibitors were effective for samples which showed high ER activities. Presently, hormonal therapy is not a standard option for endometrial cancer, because the used anti-estrogen, tamoxifen, is known to have agonistic effects on endometrial cancer.…”

Section: Individual Transcription Activity Of Er Analyzed By Adenovirmentioning

confidence: 99%

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Estrogen signaling pathway and its imaging in human breast cancer

2009

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Recent remarkable progress in hormonal therapy has provided great benefit to breast cancer patients, but it also evokes novel issues: how accurately can the efficacy of each hormonal therapy be predicted and how can hormonal therapy-resistant patients be treated? These clinically important issues must be closely related to the biological events in each cancer, such as the alteration of intracellular multiple estrogen signaling pathways and the estrogen-related cancer microenvironment, which has recently revealed by molecular biological studies on estrogen and its receptors. However, the estrogen signaling status in individual breast cancers has not been clarified yet. Here we present the context of these issues and introduce our study of new tools which enable the visualization of estrogen signals in individual cancers. The assessment of estrogen receptor (ER)-a activity in individual cancers or ER-activating ability of the cancer microenvironment in each breast cancer patient revealed several new findings and interesting observations. We hope that these approaches provide new clues about the estrogen-dependent mechanisms of breast cancer development, and will be useful to advance the diagnosis and treatment of breast cancer patients. (Cancer Sci 2009; 100: 1773-1778) Estrogen receptor and hormonal therapy in breast cancer E strogen controls various physiological functions in many target tissues, and is also involved in diseases such as breast cancer, endometrial cancer, vascular disease, osteoporosis, and others. In particular, breast cancer is well recognized to be a crucial tumor in which estrogen and its receptor (ER) regulate development and progression in most cases, and are therefore the most important and effective targets for the therapy of breast cancer.(1) In this article, ER refers to estrogen receptor α unless specified.The efficacy of hormonal therapies targeting estrogen and ER has been established in numerous clinical trials. Current hormonal therapies are performed by two main strategies: inhibition of ER functions by anti-estrogens and deprivation of estrogen production by luteinizing hormone-releasing hormone agonist (pre-menopause) or aromatase inhibitor (post-menopause). Prediction of the efficiency of these therapies has involved using classical molecular biomarkers such as ERα and progesterone receptor.(2) However, approximately one-third of ER-positive patients do not respond to endocrine therapy, while some ER-negative patients are responsive.(3) These discrepancies could result from different estrogenrelated intracellular signaling pathways in breast cancer cells.One of the approaches to analyze the estrogen signaling status in breast cancer is expression profiling of estrogen-regulated genes in cancer cells. Comprehensive gene expression analysis, such as DNA microarray, may be a useful tool to address this issue. So far, we have analyzed estrogen-responsive gene expression profiles among ER-positive cancer cells using comprehensive DNA microarray (4) and, based on the obtained informa...

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Section: Estrogen Signaling In the Cancer Microenvironmentsupporting

confidence: 69%

Section: Imaging Of Transcription Activity Of Nuclear Receptormentioning

confidence: 99%

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Estrogen signaling pathway and its imaging in human breast cancer

2009

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“…Ishikawa, RL95-2, MCF-7, and 3T3-L1 cells were cultured in RPMI 1640 (Life Technologies) supplemented with 10% fetal bovine serum (BioWest), penicillin (100 units/mL), streptomycin (100 μg/mL), and amphotericin (250 ng/mL growth medium). Primary stromal cells employed in this study were designated #3, #11, and #16 and were isolated from human endometrial carcinoma tissue samples by collagenase treatment and maintained in RPMI 1640 with 10% fetal bovine serum, penicillin (100 units/mL), streptomycin (100 μg/mL), and amphotericin as described previously (13). mRNA expressions of aromatase and 17β-HSD type 2 in stromal cells were as follows: aromatase (+) and 17β-HSD type 2 (-) in #3 and aromatase (+) and 17β-HSD type 2 (+) in both #11 and #16.…”

Section: Methodsmentioning

confidence: 99%

Local Biosynthesis of Estrogen in Human Endometrial Carcinoma through Tumor-Stromal Cell Interactions

Takahashi-Shiga

Utsunomiya

Miki

et al. 2009

Clinical Cancer Research

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Purpose: The metabolism and synthesis of intratumoral estrogens are thought to play a very important role in the etiology and progression of endometrial carcinoma. Aromatase is a key enzyme in the conversion of androgens to estrogens, and aromatase localization studies have reported that aromatase immunoreactivity and mRNA were detected mainly in stromal cells. However, the effect of tumor-stromal interactions on local estrogen biosynthesis in endometrial carcinomas remains largely unknown. Experimental Design: The endometrial carcinoma cell lines (Ishikawa and RL95-2) and breast carcinoma cell line (MCF-7) were cocultured with stromal cells isolated from endometrial carcinomas, and aromatization activity was measured using liquid chromatography-tandem mass spectrometry. We then confirmed the local biosynthesis of estrogens and tumor-stromal interactions on aromatase activity in Ishikawa and RL95-2 cells. In addition, we also examined the effects of aromatase inhibitors on cell proliferation. Results: Aromatase activity was significantly higher in cocultures with Ishikawa or RL95-2 than in each monoculture, respectively. Estrone (E 1 ) concentrations were significantly higher than estradiol (E 2 ) concentrations in Ishikawa and RL95-2 cells, whereas E 2 was significantly higher than E 1 in MCF-7 cells. Cell proliferation was significantly inhibited in Ishikawa and RL95-2 cell cultures treated with aromatase inhibitors compared with control cultures. Conclusions: These results indicate the contribution of not only E 2 but also E 1 to cancer cell proliferation in endometrial carcinoma. Our study may provide important information on metabolism and synthesis of intratumoral estrogens with regard to the etiology and progression of endometrial carcinoma, thus helping to achieve improved clinical responses in patients with endometrial carcinoma, who are treated with aromatase inhibitors. (Clin Cancer Res 2009;15(19):6028-34) Endometrial carcinoma is one of the most common malignancies in developed countries, and its incidence has increased (1). In situ estrogen metabolism, including synthesis and degradation, has recently been thought to play a very important role in the development and progression of various human estrogen-dependent neoplasms. The results of several studies have shown that the concentration of estradiol (E 2 ) in endometrial carcinoma tissue was significantly higher than the concentration in normal endometrium (2). Our results from a previous study were generally consistent with those of other investigations; we found that E 2 , estrone (E 1 ), and testosterone levels in tumor tissues were several times higher than concentrations measured in serum (3). These findings indicate that intratumoral estrogen metabolism and synthesis is important in the etiology and progression of endometrial carcinoma.Intratumoral production of estrogen occurs as a result of the aromatization of androgens such as androstenedione and testosterone into estrogens, and it is catalyzed by the cytochrome P450 aromatas...

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“…We previously examined whether estrogen biosynthesis in the tumor microenvironment promoted endometrial carcinoma or not. In order to study the contribution of stromal cells to estrogen signaling pathways in endometrial carcinoma, we examined reporter cells stably transfected with the estrogen response element (ERE) fused to the destabilized green fluorescent protein (GFP) gene (Matsumoto et al 2008). In this system, the ERE of carcinoma cells was activated to a variable extent by intratumoral stromal cells isolated from endometrial carcinoma.…”

Section: :7mentioning

confidence: 99%

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

Itō¹,

Miki²,

Suzuki³

et al. 2016

Endocrine-Related Cancer

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In situ estrogen biosynthesis is considered to play pivotal roles in the development and progression of human endometrial carcinoma. However, the biological roles of androgen have remained virtually unknown. Various epidemiological studies have revealed that elevated serum androgen levels are generally associated with an increased risk of developing endometrial carcinoma; however, studies directly examining androgens in carcinoma tissues are relatively rare and reviews summarizing this information are scarce. Therefore, we summarized recent studies on androgens in endometrial carcinoma, especially focusing androgen actions and in situ androgen biosynthesis. Among the enzymes required for local biosynthesis of androgen, 17β-hydroxysteroid dehydrogenase type 5 (conversion from androstenedione to testosterone) and 5α-reductase (reduction of testosterone to dihydrotestosterone (DHT)) are the principal enzymes involved in the formation of biologically most potent androgen, DHT. Both enzymes and androgen receptor were expressed in endometrial carcinoma tissues, and in situ production of DHT has been reported to exist in endometrial carcinoma tissues. However, testosterone is not only a precursor of DHT production, but also a precursor of estradiol synthesis, as a substrate of the aromatase enzyme. Therefore, aromatase could be another key enzyme serving as a negative regulator for in situ production of DHT by reducing amounts of the precursor. In an in vitro study, DHT was reported to exert antiproliferative effects on endometrial carcinoma cells. Intracrine mechanisms of androgens, the downstream signals of AR, which are directly related to anticancer progression, and the clinical significance of DHT-AR pathway in the patients with endometrial carcinoma have, however, not been fully elucidated.

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Estrogen signaling ability in human endometrial cancer through the cancer-stromal interaction

Cited by 40 publications

References 38 publications

Estrogen signaling pathway and its imaging in human breast cancer

Estrogen signaling pathway and its imaging in human breast cancer

Local Biosynthesis of Estrogen in Human Endometrial Carcinoma through Tumor-Stromal Cell Interactions

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

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