Targeting BIG3-PHB2 interaction to overcome tamoxifen resistance in breast cancer cells

被引：65

作者：

Yoshimaru, Tetsuro ^{[1
]}

Komatsu, Masato ^{[1
]}

Matsuo, Taisuke ^{[1
]}

Chen, Yi-An ^{[2
]}

Murakami, Yoichi ^{[2
]}

Mizuguchi, Kenji ^{[2
]}

Mizohata, Eiichi ^{[3
]}

Inoue, Tsuyoshi ^{[3
]}

Akiyama, Miki ^{[4
]}

Yamaguchi, Rui ^{[5
]}

Imoto, Seiya ^{[6
]}

Miyano, Satoru ^{[6
]}

Miyoshi, Yasuo ^{[7
]}

Sasa, Mitsunori ^{[8
]}

Nakamura, Yusuke ^{[4
,9
]}

Katagiri, Toyomasa ^{[1
]}

机构：

[1] Univ Tokushima, Inst Genome Res, Div Genome Med, Tokushima 7708503, Japan

[2] Natl Inst Biomed Innovat, Ibaraki, Osaka 5670085, Japan

[3] Osaka Univ, Grad Sch Engn, Dept Appl Chem, Suita, Osaka 5650871, Japan

[4] Univ Tokyo, Mol Med Lab, Minato Ku, Tokyo 1088639, Japan

[5] Univ Tokyo, Lab Sequence Anal, Minato Ku, Tokyo 1088639, Japan

[6] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab DNA Informat Anal,Minato Ku, Tokyo 1088639, Japan

[7] Hyogo Coll Med, Dept Surg, Div Breast & Endocrine Surg, Nishinomiya, Hyogo 6638501, Japan

[8] Tokushima Breast Care Clin, Dept Surg, Tokushima 7700052, Japan

[9] Univ Chicago, Dept Med & Surg, Chicago, IL 60637 USA

来源：

NATURE COMMUNICATIONS | 2013年 / 4卷

关键词：

ESTROGEN-RECEPTOR-ALPHA; SURGICAL ADJUVANT BREAST; GENE-TRANSCRIPTION; IN-VIVO; ACTIVATION; PHOSPHORYLATION; MECHANISMS; STIMULATION; PROGRESSION; PREDICTION;

D O I：

10.1038/ncomms3443

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The acquisition of endocrine resistance is a common obstacle in endocrine therapy of patients with oestrogen receptor-alpha (ER alpha)-positive breast tumours. We previously demonstrated that the BIG3-PHB2 complex has a crucial role in the modulation of oestrogen/ER alpha signalling in breast cancer cells. Here we report a cell-permeable peptide inhibitor, called ERAP, that regulates multiple ERa-signalling pathways associated with tamoxifen resistance in breast cancer cells by inhibiting the interaction between BIG3 and PHB2. Intrinsic PHB2 released from BIG3 by ERAP directly binds to both nuclear-and membrane-associated ER alpha, which leads to the inhibition of multiple ER alpha-signalling pathways, including genomic and non-genomic ERa activation and ER alpha phosphorylation, and the growth of ER alpha-positive breast cancer cells both in vitro and in vivo. More importantly, ERAP treatment suppresses tamoxifen resistance and enhances tamoxifen responsiveness in ER alpha-positive breast cancer cells. These findings suggest inhibiting the interaction between BIG3 and PHB2 may be a new therapeutic strategy for the treatment of luminal-type breast cancer.

引用

页数：13

共 55 条

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