Breast cancer resistance to antiestrogens is enhanced by increased ER degradation and ERBB2 expression

Tomohiro Shibata, Kosuke Watari, Hiroto Izumi, Akihiko Kawahara, Satoshi Hattori, Chihiro Fukumitsu, Yuichi Murakami, Ryuji Takahashi, Uhi Toh, Ken Ichi Ito, Shigehiro Ohdo, Maki Tanaka, Masayoshi Kage, Michihiko Kuwano, Mayumi Ono

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)545-556
Number of pages12
JournalCancer Research
Volume77
Issue number2
DOIs
Publication statusPublished - Jan 15 2017

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Estrogen Receptor Modulators
Estrogen Receptors
Breast Neoplasms
Tamoxifen
Drug Resistance
Transcriptional Activation
Transcription Factors
Phosphorylation
Therapeutics
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Breast cancer resistance to antiestrogens is enhanced by increased ER degradation and ERBB2 expression. / 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.

In: Cancer Research, Vol. 77, No. 2, 15.01.2017, p. 545-556.

Research output: Contribution to journalArticle

Shibata, T, Watari, K, Izumi, H, Kawahara, A, Hattori, S, Fukumitsu, C, Murakami, Y, Takahashi, R, Toh, U, Ito, KI, Ohdo, S, Tanaka, M, Kage, M, Kuwano, M & Ono, M 2017, 'Breast cancer resistance to antiestrogens is enhanced by increased ER degradation and ERBB2 expression' Cancer Research, vol. 77, no. 2, pp. 545-556. https://doi.org/10.1158/0008-5472.CAN-16-1593
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. / Breast cancer resistance to antiestrogens is enhanced by increased ER degradation and ERBB2 expression. In: Cancer Research. 2017 ; Vol. 77, No. 2. pp. 545-556.
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