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Activation of an Estrogen/ Estrogen Receptor Signaling by BIG3 Through Its Inhibitory Effect on Nuclear Transport of PHB2/REA in Breast Cancer

Jung-Won Kim¹, Miki Akiyama¹, Jae-Hyun Park¹, Meng-Lay Lin¹, Arata Shimo¹, Tomomi Ueki¹, Yataro Daigo¹, Tatsuhiko Tsunoda¹, Toshihiko Nishidate², Yusuke Nakamura¹ & Toyomasa Katagiri¹

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1. Institute of Medical Science, University of Tokyo, Lab. of Molecular Medicine, Human Genome Center
2. The University of Tokyo, Institute of Medical Science, Human Genome Center

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Document Type:

Manuscript

Date:

Received 30 January 2009 04:54 UTC; Posted 30 January 2009

Subjects:

Cancer, Genetics & Genomics

Tags:

• molecular-target
• breast cancer
• estrogen receptor

Abstract:

Breast cancer is known to be a hormone-dependent disease, and estrogens through an interaction with estrogen receptor (ER) enhance the proliferative and metastatic activity of breast tumor cells. Here we show a critical role of transactivation of BIG3, brefeldin A-inhibited guanine nucleotide-exchange protein 3, in activation of the estrogen/ER signaling in breast cancer cells. Knocking-down of BIG3 expression with small-interfering RNA (siRNA) drastically suppressed the growth of breast cancer cells. Subsequent co-immunoprecipitation and immunoblotting assays revealed an interaction of BIG3 with prohibitin 2/repressor of estrogen receptor activity (PHB2/REA). When BIG3 was absent, stimulation of estradiol caused the translocation of PHB2/REA to the nucleus, enhanced the interaction of PHB2/REA and ERα, and resulted in suppression of the ERα; transcriptional activity. On the other hand, when BIG3 was present, BIG3 trapped PHB2/REA in cytoplasm and inhibited its nuclear translocation, and caused enhancement of ERα; transcriptional activity. Our results imply that BIG3 overexpression is one of the important mechanisms causing the activation of the estrogen/ERα; signaling pathway in the hormone-related growth of breast cancer cells.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Kim, Jung-Won, Akiyama, Miki, Park, Jae-Hyun, Lin, Meng-Lay, Shimo, Arata, Ueki, Tomomi, Daigo, Yataro, Tsunoda, Tatsuhiko, Nishidate, Toshihiko, Nakamura, Yusuke, and Katagiri, Toyomasa. Activation of an Estrogen/ Estrogen Receptor Signaling by BIG3 Through Its Inhibitory Effect on Nuclear Transport of PHB2/REA in Breast Cancer. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2009.2834.1> (2009)

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