title: Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma.
abstract: Aromatase inhibitors (AI) are commonly used to treat postmenopausal estrogen-receptor (ER)-positive breast carcinoma. However, resistance to AI is sometimes acquired, and the molecular mechanisms underlying such resistance are largely unclear. Recent studies suggest that AI treatment increases androgen activity during estrogen deprivation in breast carcinoma, but the role of the androgen receptor (AR) in breast carcinoma is still a matter of controversy. The purpose of this study is to examine the potential correlation between the AR- and AI-resistant breast carcinoma. To this end, we performed immunohistochemical analysis of 21 pairs of primary breast carcinoma and corresponding AI-resistant recurrent tissue samples and established two stable variant cell lines from ER-positive T-47D breast carcinoma cell line as AI-resistance models and used them in in vitro experiments. Immunohistochemical analysis demonstrated that the expression of prostate-specific antigen (PSA) and Ki-67 were significantly higher and ER and progesterone receptor (PR) were lower in recurrent lesions compared to the corresponding primary lesions. Variant cell lines overexpressed AR and PSA and exhibited neither growth response to estrogen nor expression of ER. Androgen markedly induced the proliferation of these cell lines. In addition, the expression profile of androgen-induced genes was markedly different between variant and parental cell lines as determined by microarray analysis. These results suggest that in some cases of ER-positive breast carcinoma, tumor cells possibly change from ER-dependent to AR-dependent, rendering them resistant to AI. AR inhibitors may thus be effective in a selected group of patients.
authors.affiliation: Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Fujii
authors.affiliation: Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hanamura
authors.affiliation: Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Gohno
authors.affiliation: Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shibahara
authors.affiliation: Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Ina-machi, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Breast and Thyroid Surgery, Iwate Prefectural Central Hospital, Morioka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ohnuki
authors.affiliation: Department of Breast Oncology, Miyagi Cancer Center Hospital, Natori, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kakugawa
authors.affiliation: Department of Surgery, Tohoku Kosai Hospital, Sendai, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hirakawa
authors.affiliation: Department of Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
authors.affiliation: Department of Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Ohuchi
authors.affiliation: Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: shin@med.tohoku.ac.jp.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hayashi
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D019394:Ki-67 Antigen; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Androgen receptor; Aromatase inhibitor-resistance; Breast cancer; DDC; PSA