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Aromatase Localization in Human Breast Cancer Tissues: Possible Interactions between Intratumoral Stromal and Parenchymal Cells

Departments of ¹ Pathology and ² Surgical Oncology, Tohoku University Graduate School of Medicine, Divisions of ³ Pathology and ⁴ Molecular Medical Technology, School of Medicine, Course of Health Sciences, Tohoku University, ⁵ Department of Pathology, Tohoku University Hospital, and ⁶ Department of Surgery, Tohoku Kosai Hospital, Sendai, Japan; ⁷ Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan; ⁸ Pharmaceutical Technology Department, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan; ⁹ Research Development Department, Teizo Medical Co., Ltd., Kanagawa, Japan; and ¹⁰ Novartis Institutes for BioMedical Research Basel, Oncology Research, Basel, Switzerland

Requests for reprints: Hironobu Sasano, Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi-ken 980-8575, Japan. Phone: 81-22-717-8050; Fax: 81-22-717-8051; E-mail: hsasano{at}patholo2.med.tohoku.ac.jp.

Aromatase is a key enzyme in intratumoral estrogen production required for the production of estrogens through the conversion of serum androgens in postmenopausal breast cancer patients. There have been, however, controversies regarding the intratumoral localization of aromatase in human breast carcinoma tissues. Therefore, we have first examined the intratumoral localization of aromatase mRNA/protein in 19 breast carcinomas using laser capture microdissection/quantitative reverse transcription-PCR (RT-PCR) and immunohistochemistry. Aromatase mRNA and protein were detected in both intratumoral stromal and parenchymal cells in breast carcinoma tissues. Subsequent microarray expression profiling and clustering analyses, in addition to quantitative RT-PCR studies, showed a significant positive correlation between aromatase and estrogen-related receptor mRNA expression in isolated carcinoma cells. We further examined an interaction between stromal cells isolated from human breast carcinoma tissues and breast carcinoma cell lines using a coculture system to study the biological characteristic of aromatase expression in carcinoma cells. Aromatase mRNA and enzyme activity and 17ß-hydroxysteroid dehydrogenase type 1 mRNA in breast carcinoma cell lines, including MCF-7 and SK-BR-3 cells, were up-regulated in the presence of patient-derived 32N or 74T intratumoral stromal cells. The results from steroid conversion assays were also consistent with the findings above. The results of our study also showed that aromatase inhibitors were more effective in inhibiting aromatization induced by coculture in MCF-7 than that in stromal 32N. The examination of the localization of aromatase and its regulation, including the interactions existing between different cell types in human breast carcinoma tissues, may provide important information as to achieving better clinical response to aromatase inhibitors in breast cancer patients. [Cancer Res 2007;67(8):3945–54]

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