Breast Cancer Resistance to Antiestrogens Is Enhanced by Increased ER Degradation and ERBB2 Expression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-01, Vol.77 (2), p.545-556
• Main Authors: Shibata, Tomohiro, Watari, Kosuke, Izumi, Hiroto, Kawahara, Akihiko, Hattori, Satoshi, Fukumitsu, Chihiro, Murakami, Yuichi, Takahashi, Ryuji, Toh, Uhi, Ito, Ken-Ichi, Ohdo, Shigehiro, Tanaka, Maki, Kage, Masayoshi, Kuwano, Michihiko, Ono, Mayumi
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antiestrogens; Blotting, Western; Breast cancer; Breast Neoplasms - metabolism; Cell Line, Tumor; Degradation; Drug resistance; Drug Resistance, Neoplasm - physiology; Endocrine therapy; ErbB-2 protein; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen Receptor Modulators - pharmacology; Estrogen receptors; Estrogens; Female; Fulvestrant; Gene Expression Regulation, Neoplastic - physiology; Humans; Immunoprecipitation; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Phosphorylation; Proteasomes; Receptor, ErbB-2 - biosynthesis; Receptors, Estrogen - metabolism; Tamoxifen; Tamoxifen - pharmacology; Transcription activation; Tumors; Xenograft Model Antitumor Assays; Y-Box-Binding Protein 1 - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-1593

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. Cancer Res; 77(2); 545-56. ©2016 AACR.