TY - JOUR
T1 - Breast cancer resistance to antiestrogens is enhanced by increased ER degradation and ERBB2 expression
AU - Shibata, Tomohiro
AU - Watari, Kosuke
AU - Izumi, Hiroto
AU - Kawahara, Akihiko
AU - Hattori, Satoshi
AU - Fukumitsu, Chihiro
AU - Murakami, Yuichi
AU - Takahashi, Ryuji
AU - Toh, Uhi
AU - Ito, Ken Ichi
AU - Ohdo, Shigehiro
AU - Tanaka, Maki
AU - Kage, Masayoshi
AU - Kuwano, Michihiko
AU - Ono, Mayumi
N1 - Funding Information:
We thank Kimitoshi Kohno (University of Occupational and Environmental Health, Kitakyushu, Japan) for fruitful discussions. This work is supported by JSPS KAKENHI grant number 15J03033 (T. Shibata), the Fukuoka Foundation for Sound Health Cancer Research Fund (T. Shibata), the Life Science Foundation of Japan (M. Ono), and St. Mary's Institute of Health Sciences (K. Watari, M. Kuwano, and M. Ono). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2017/1/15
Y1 - 2017/1/15
N2 - Endocrine therapies effectively improve the outcomes of patients with estrogen receptor (ER)-positive breast cancer. However, the emergence of drug-resistant tumors creates a core clinical challenge. In breast cancer cells rendered resistant to the antiestrogen fulvestrant, we defined causative mechanistic roles for the transcription factor YBX1 and the levels of ER and the ERBB2 receptor. Enforced expression of YBX1 in parental cells conferred resistance against tamoxifen and fulvestrant in vitro and in vivo. Furthermore, YBX1 overexpression was associated with decreased and increased levels of ER and ERBB2 expression, respectively. In antiestrogen-resistant cells, increased YBX1 phosphorylation was associated with a 4-fold higher degradation rate of ER. Notably, YBX1 bound the ER, leading to its accelerated proteasomal degradation, and induced the transcriptional activation of ERBB2. In parallel fashion, tamoxifen treatment also augmented YBX1 binding to the ERBB2 promoter to induce increased ERBB2 expression. Together, these findings define a mechanism of drug resistance through which YBX1 contributes to antiestrogen bypass in breast cancer cells.
AB - Endocrine therapies effectively improve the outcomes of patients with estrogen receptor (ER)-positive breast cancer. However, the emergence of drug-resistant tumors creates a core clinical challenge. In breast cancer cells rendered resistant to the antiestrogen fulvestrant, we defined causative mechanistic roles for the transcription factor YBX1 and the levels of ER and the ERBB2 receptor. Enforced expression of YBX1 in parental cells conferred resistance against tamoxifen and fulvestrant in vitro and in vivo. Furthermore, YBX1 overexpression was associated with decreased and increased levels of ER and ERBB2 expression, respectively. In antiestrogen-resistant cells, increased YBX1 phosphorylation was associated with a 4-fold higher degradation rate of ER. Notably, YBX1 bound the ER, leading to its accelerated proteasomal degradation, and induced the transcriptional activation of ERBB2. In parallel fashion, tamoxifen treatment also augmented YBX1 binding to the ERBB2 promoter to induce increased ERBB2 expression. Together, these findings define a mechanism of drug resistance through which YBX1 contributes to antiestrogen bypass in breast cancer cells.
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U2 - 10.1158/0008-5472.CAN-16-1593
DO - 10.1158/0008-5472.CAN-16-1593
M3 - Article
C2 - 27879270
AN - SCOPUS:85018162335
SN - 0008-5472
VL - 77
SP - 545
EP - 556
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -
