title: Breast Cancer Resistance to Antiestrogens Is Enhanced by Increased ER Degradation and ERBB2 Expression.
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. Cancer Res; 77(2); 545-56. ©2016 AACR.
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Watari
authors.affiliation: Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kawahara
authors.affiliation: Biostatistics Center, Kurume University, Kurume, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hattori
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Fukumitsu
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.|Cancer Translational Research Center, St. Mary's Institute of Health Sciences, Kurume, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Breast Care Center, Kyushu Medical Center, Fukuoka, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Surgery, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Uhi
authors.initials: U
authors.lastname: Toh
authors.affiliation: Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Ito
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
authors.affiliation: Kurume General Hospital, Japan Community Health Care Organization (JCHO), Kurume, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kage
authors.affiliation: Cancer Translational Research Center, St. Mary's Institute of Health Sciences, Kurume, Japan.
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. mono@phar.kyushu-u.ac.jp.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism*
chemical_list: D004958:Estradiol; D020847:Estrogen Receptor Modulators; D000077267:Fulvestrant; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C508053:ERBB2 protein, human