Aromatase Expression in Stromal Cells of Endometrioid Endometrial Cancer Correlates with Poor Survival

Segawa, Tomoya; Shozu, Makio; Murakami, Kouich; Kasai, Tokuzo; Shinohara, Kazunori; Nomura, Kohji; Ohno, Satoshi; Inoue, Masakí

doi:10.1158/1078-0432.ccr-04-1859

Cited by 50 publications

(46 citation statements)

References 37 publications

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“…Immunohistochemical studies of the biosynthesis and metabolism of estrogen in EC confirm that estrogen-metabolizing enzymes, such as 17b-HSD types 2 and 5, are present in the cytoplasm of tumor cells but not stromal cells (Ito et al 2006). By contrast, aromatase is more highly expressed in stromal than tumor cells (Watanabe et al 1995, Sasano et al 1996, and its expression is correlated with poor survival (Segawa et al 2005). To date, there has been no direct confirmation of stromal-tumor interactions mediated by estrogen signaling and the transactivation of ERE by endometrial stromal cells.…”

Section: Discussionmentioning

confidence: 99%

“…The mRNA and protein of aromatase are detectable in EC but are absent in disease-free endometrium (Bulun et al 1994, Watanabe et al 1995. Furthermore, the endometrial cancer patients with aromatase-positive stromal cells have poor survival prognosis compared with patients with aromatase-negative stromal cells (Segawa et al 2005). This evidence also suggests that aromatase is a key enzyme in the etiology of EC; however, the participation of local estrogen in the activation of ER in individual EC tumor cells has not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

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

Matsumoto

Yamaguchi

Seino

et al. 2008

Endocrine Related Cancer

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The estrogen pathway plays an important role in the etiology of human endometrial carcinoma (EC). We examined whether estrogen biosynthesis in the tumor microenvironment promotes endometrial cancer. To examine the contribution of stromal cells to estrogen signaling in EC, we used reporter cells stably transfected with the estrogen response element (ERE) fused to the destabilized green fluorescent protein (GFP) gene. In this system, the endometrial cancer stromal cells from several patients activated the ERE of cancer cells to a variable extent. The GFP expression level increased when testosterone, a substrate for aromatase, was added. The effect was variably inhibited by aromatase inhibitors (AIs), although the response to AIs varied among patients. These results suggest that GFP expression is driven by estrogen synthesized by aromatase in the endometrial cancer stromal cells. In a second experiment, we constructed an adenovirus reporter vector containing the same construct as the reporter cells described above, and visualized endogenous ERE activity in primary culture cancer cells from 15 EC specimens. The GFP expression levels varied among the cases, and in most primary tissues, ERE activities were strongly inhibited by a pure anti-estrogen, fulvestrant. Interestingly, a minority of primary tissues in endometrial cancer showed ERE activity independent of the estrogen-ER pathway. These results suggest that AI may have some therapeutic value in EC; however, the hormonal microenvironment must be assessed prior to initiating therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Matsumoto

Yamaguchi

Seino

et al. 2008

Endocrine Related Cancer

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“…Aromatase expression was significant, both at the protein and mRNA levels, at the site of frank invasion in endometrial carcinoma, suggesting induction of aromatase expression by tumor-stromal interactions. Recently, Segawa et al reported a significant correlation between aromatase immunoreactivity in stromal cells and poor prognosis in 55 patients with endometrial carcinoma [21]. This positive linkage indicates that local aromatase expression plays a role in tumor progression through the formation of in situ estrogens.…”

Section: ) Aromatasementioning

confidence: 97%

“…Aromatase is a key enzyme in the synthesis of estrogens and its levels in breast carcinoma tissues have been found to be significantly higher than those in benign breast lesions [5]. Expression of aromatase has also been detected in human endometrial carcinoma [20,21]. Our laboratories previously reported marked aromatase immunoreactivity and mRNA, mainly in the stromal cells or fibroblasts of endometrioid endometrial carcinoma, but not in normal or hyperplastic endometrium [20] (Fig.…”

Section: ) Aromatasementioning

confidence: 99%

Biological Roles of Estrogen and Progesterone in Human Endometrial Carcinoma - New developments in potential endocrine therapy for endometrial cancer -

et al. 2007

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Abstract. Endometrial carcinoma is one of the most common female pelvic malignancies. It is well known that uterine endometrial cell proliferation is under the control of both estrogen and progesterone. In this review, results of the recent studies on the biosynthesis and action of estrogen and progestin in normal endometrium and its disorders will be summarized and the new aspects of hormonal therapies in the patients with endometrial carcinoma will be discussed including its future prospectives. We reported that the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are markedly different between human breast and endometrial carcinoma, although both of them are considered "estrogen-dependent malignancies". In addition, the biological significance of Progesterone receptor (PR) isoforms is considered to differ between endometrial and breast carcinomas. Clinical data concerning Hormone replacement therapy (HRT) and estrogen-dependent cancer risk also support these findings. These basic and clinical findings help to understand the biology and provide the new knowledge for prevention, diagnosis and treatment of human endomerial carcinoma. Specific endocrine treatment of endometrial carcinoma should be explored in future, although aromatase inhibitors are the most effective endocrine treatments of estrogen-responsive breast carcinoma. Retinoid, metabolities of vitamin A, and synthetic peroxisome proliferator-activated receptor (PPAR) γ ligands, which have been used for the treatment of insulin resistance in type II diabetes mellitus, may be the important candidates as drugs not only for prevention but also for possible endocrine treatment of endometrial carcinoma.

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“…In addition, a significant correlation was detected between aromatase expression in stromal cells and poor prognosis in the patients with endometrial carcinoma (Segawa et al 2005), although several studies reported that aromatase expression was demonstrated in carcinoma and stromal cells together (Segawa et al 2005, Jongen et al 2009, Che et al 2014. It is very important to consider in vitro stromal-carcinoma cell interactions when studying aromatase expression in vitro.…”

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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Aromatase Expression in Stromal Cells of Endometrioid Endometrial Cancer Correlates with Poor Survival

Cited by 50 publications

References 37 publications

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

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

Biological Roles of Estrogen and Progesterone in Human Endometrial Carcinoma - New developments in potential endocrine therapy for endometrial cancer -

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

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