Kim Jung-Won, Akiyama Miki, Park Jae-Hyun, Lin Meng-Lay, Shimo Arata, Ueki Tomomi, Daigo Yataro, Tsunoda Tatsuhiko, Nishidate Toshihiko, Nakamura Yusuke, Katagiri Toyomasa
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Cancer Sci. 2009 Aug;100(8):1468-78. doi: 10.1111/j.1349-7006.2009.01209.x. Epub 2009 May 6.
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 coimmunoprecipitation 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 ERalpha, and resulted in suppression of the ERalpha transcriptional activity. On the other hand, when BIG3 was present, BIG3 trapped PHB2/REA in the cytoplasm and inhibited its nuclear translocation, and caused enhancement of ERalpha transcriptional activity. Our results imply that BIG3 overexpression is one of the important mechanisms causing the activation of the estrogen/ERalpha signaling pathway in the hormone-related growth of breast cancer cells.
已知乳腺癌是一种激素依赖性疾病，雌激素通过与雌激素受体（ER）相互作用，增强乳腺肿瘤细胞的增殖和转移活性。在此我们展示了BIG3（布雷菲德菌素A抑制的鸟嘌呤核苷酸交换蛋白3）的反式激活在乳腺癌细胞雌激素/ER信号激活中的关键作用。用小干扰RNA（siRNA）敲低BIG3表达可显著抑制乳腺癌细胞的生长。随后的免疫共沉淀和免疫印迹分析揭示了BIG3与抑制素2/雌激素受体活性阻遏物（PHB2/REA）之间的相互作用。当不存在BIG3时，雌二醇刺激导致PHB2/REA易位至细胞核，增强了PHB2/REA与ERα的相互作用，并导致ERα转录活性受到抑制。另一方面，当存在BIG3时，BIG3将PHB2/REA截留在细胞质中并抑制其核易位，从而导致ERα转录活性增强。我们的结果表明，BIG3过表达是在乳腺癌细胞激素相关生长过程中导致雌激素/ERα信号通路激活的重要机制之一。
