Activation of an estrogen/estrogen receptor signaling by BIG3 through its inhibitory effect on nuclear transport of PHB2/REA in breast cancer.
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.
Kim
Jung-Won
JW
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Akiyama
Miki
M
Park
Jae-Hyun
JH
Lin
Meng-Lay
ML
Shimo
Arata
A
Ueki
Tomomi
T
Daigo
Yataro
Y
Tsunoda
Tatsuhiko
T
Nishidate
Toshihiko
T
Nakamura
Yusuke
Y
Katagiri
Toyomasa
T
D021581:Active Transport, Cell Nucleus; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004967:Estrogens / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D000091402:Prohibitins; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D000099222:betaIG-H3 Protein
D004967:Estrogens; D016326:Extracellular Matrix Proteins; D005456:Fluorescent Dyes; D049452:Green Fluorescent Proteins; D000091402:Prohibitins; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C000717331:PHB2 protein, human; C485184:enhanced green fluorescent protein