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: Rika Fujii, Toru Hanamura, Takashi Suzuki, Tatsuyuki Gohno, Yukiko Shibahara, Toshifumi Niwa, Yuri Yamaguchi, Koji Ohnuki, Yoichiro Kakugawa, Hisashi Hirakawa, Takanori Ishida, Hironobu Sasano, Noriaki Ohuchi, Shin-ichi Hayashi
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 144 Pt B Pg. 513-22 (Oct 2014) ISSN: 1879-1220 [Electronic] England
• PMID: 25178713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• AR protein, human
• Antineoplastic Agents
• Aromatase Inhibitors
• Ki-67 Antigen
• Receptors, Androgen
• Receptors, Estrogen
• Receptors, Progesterone
• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen

Topics

• Aged
• Antineoplastic Agents (therapeutic use)
• Aromatase Inhibitors (therapeutic use)
• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Female
• Gene Expression Profiling
• Humans
• Kallikreins (metabolism)
• Ki-67 Antigen (metabolism)
• Middle Aged
• Prostate-Specific Antigen (metabolism)
• Receptors, Androgen (metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)