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Takashi Suzuki
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Akio Inoue
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Yasuhiro Miki
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Takuya Moriya
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Jun-ichi Akahira
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Takanori Ishida
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Hisashi Hirakawa
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Yuri Yamaguchi
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Shin-ichi Hayashi
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Hironobu Sasano
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Early growth responsive gene 3 (EGR3) is a zinc-finger transcription factor and plays important roles in cellular growth and differentiation. We recently demonstrated estrogen-mediated induction of EGR3 in breast carcinoma cells. However, EGR3 has not yet been examined in breast carcinoma tissues and its significance remains unknown. Therefore, in this study, we examined biological functions of EGR3 in the breast carcinoma by immunohistochemistry, in vitro study, and nude mouse xenograft model. EGR3 immunoreactivity was detected in carcinoma cells in 99 (52%) out of 190 breast carcinoma tissues and was associated with the mRNA level. EGR3 immunoreactivity was positively associated with lymph node status, distant metastasis into other organs, estrogen receptor α, or EGR3 immunoreactivity in asynchronous recurrent lesions in the same patients, and was negatively correlated with tubule formation. EGR3 immunoreactivity was significantly associated with an increased risk of recurrence and adverse clinical outcome by both uni- and multivariate analyses. Egr3-expressing transformant cell lines derived from MCF-7 Tet-Off cells (Eg-10 and Eg-11) significantly enhanced the migration and invasion properties according to the treatment of doxycyclin, but did not significantly change the cell proliferation. Moreover, Eg-11 cells injected into athymic mice irregularly invaded into the adjacent peritumoral tissues, although Clt-7, which was stably transfected with empty vector as a control, demonstrated a well-circumscribed tumor. Eg-11 cells were significantly associated with invasive components and less tubule formation in the xenograft model. These results suggest that EGR3 plays an important role in estrogen-meditated invasion and is an independent prognostic factor in breast carcinoma.

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Rie Shibuya
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Takashi Suzuki
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Yasuhiro Miki
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Kimako Yoshida
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Takuya Moriya
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Katsuhiko Ono
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Jun-ichi Akahira
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Takanori Ishida Department of Pathology, Department of Surgery, Department of Surgery, Novartis Institutes for BioMedical Research Basel, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan

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Hisashi Hirakawa Department of Pathology, Department of Surgery, Department of Surgery, Novartis Institutes for BioMedical Research Basel, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan

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Dean B Evans Department of Pathology, Department of Surgery, Department of Surgery, Novartis Institutes for BioMedical Research Basel, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan

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Hironobu Sasano
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It is well known that sex steroids play important roles in the development of invasive ductal carcinoma (IDC) of the human breast. However, biological significance of sex steroids remains largely unclear in ductal carcinoma in situ (DCIS), regarded as a precursor lesion of IDC, which is partly due to the fact that the intratumoral concentration of sex steroids has not been examined in DCIS. Therefore, in this study, we first examined the intratumoral concentrations of estradiol and 5α-dihydrotestosterone (DHT) using liquid chromatography/electrospray tandem mass spectrometry in DCIS. Intratumoral concentrations of both estradiol and DHT were threefold higher in DCIS than non-neoplastic breast tissues and estrogen-producing enzymes (aromatase, steroid sulfatase, and 17β-hydroxysteroid dehydrogenase type 1 (17βHSD1)), and androgen-producing enzymes (17βHSD5 and 5α-reductase type 1 (5αRed1)) were abundantly expressed in DCIS by real-time PCR and immunohistochemical analyses. The intratumoral concentration of DHT was significantly lower in IDC than DCIS, while the expression of aromatase mRNA in carcinoma cells and intratumoral stromal cells was significantly higher in IDC than those in DCIS. Immunohistochemistry for sex steroid-producing enzymes in DCIS demonstrated that 5αRed1 immunoreactivity was positively correlated with Ki-67 labeling index and histological grade and was also associated with an increased risk of recurrence in patients with DCIS examined. Results of our study suggest that intratumoral concentrations of estradiol and DHT are increased in DCIS, which is possibly due to intratumoral production of these steroids. Therefore, estradiol and DHT may play important roles in the development of DCIS of the human breast.

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Kiyoshi Takagi Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Yasuhiro Miki Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Shuji Nagasaki Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Hisashi Hirakawa Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Yoshiaki Onodera Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Jun-ichi Akahira Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Takanori Ishida Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Mika Watanabe Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Izo Kimijima Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Shin-ichi Hayashi Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Hironobu Sasano Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Takashi Suzuki Departments of, Pathology and Histotechnology, Anatomic Pathology, Department of Surgery, Department of Surgical Oncology, Department of Pathology, Northern Fukushima Medical Center, Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan

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Sex steroids play important roles in the development of many human breast carcinomas, and aromatase inhibitors are used for the anti-estrogen therapy. Recent studies have demonstrated that aromatase suppressed 5α-dihydrotestosterone (DHT) synthesis in breast carcinoma cells, but intratumoral concentration of androgens and its significance have not been reported in the breast carcinoma patients treated with aromatase inhibitors. Therefore, we examined androgen concentrations in breast carcinoma tissues treated with exemestane, and further performed in vitro studies to characterize the significance of androgen actions. Intratumoral DHT concentration was significantly higher in breast carcinoma tissues following exemestane treatment (n=9) than those without the therapy (n=7), and 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) status was significantly altered to be positive after the treatment. Following in vitro studies showed that 17βHSD2 expression was dose dependently induced by both DHT and exemestane in T-47D breast carcinoma cells, but these inductions were not additive. DHT-mediated induction of 17βHSD2 expression was markedly suppressed by estradiol (E2) in T-47D cells. E2-mediated cell proliferation was significantly inhibited by DHT in T-47D cells, associated with an increment of 17βHSD2 expression level. These findings suggest that intratumoral androgen actions are increased during exemestane treatment. 17 β HSD2 is a potent DHT-induced gene in human breast carcinoma, and may not only be involved in anti-proliferative effects of DHT on breast carcinoma cells but also serve as a potential marker for response to aromatase inhibitor in the breast carcinoma patients.

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