title: USP9X downregulation renders breast cancer cells resistant to tamoxifen.
abstract: Tamoxifen is one of the most widely used endocrine agents for the treatment of estrogen receptor α (ERα)-positive breast cancer. Although effective in most patients, resistance to tamoxifen is a clinically significant problem and the mechanisms responsible remain elusive. To address this problem, we performed a large scale loss-of-function genetic screen in ZR-75-1 luminal breast cancer cells to identify candidate resistance genes. In this manner, we found that loss of function in the deubiquitinase USP9X prevented proliferation arrest by tamoxifen, but not by the ER downregulator fulvestrant. RNAi-mediated attenuation of USP9X was sufficient to stabilize ERα on chromatin in the presence of tamoxifen, causing a global tamoxifen-driven activation of ERα-responsive genes. Using a gene signature defined by their differential expression after USP9X attenuation in the presence of tamoxifen, we were able to define patients with ERα-positive breast cancer experiencing a poor outcome after adjuvant treatment with tamoxifen. The signature was specific in its lack of correlation with survival in patients with breast cancer who did not receive endocrine therapy. Overall, our findings identify a gene signature as a candidate biomarker of response to tamoxifen in breast cancer.
authors.affiliation: Authors' Affiliations: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands; and.
authors.forename: Hendrika M
authors.initials: HM
authors.lastname: Oosterkamp
authors.affiliation: Authors' Affiliations: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands; and.
authors.forename: E Marielle
authors.initials: EM
authors.lastname: Hijmans
authors.affiliation: Authors' Affiliations: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands; and.
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
authors.affiliation: Authors' Affiliations: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands; and.
authors.forename: Sander
authors.initials: S
authors.lastname: Canisius
authors.affiliation: Authors' Affiliations: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands; and.
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands r.bernards@nki.nl w.zwart@nki.nl.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
authors.affiliation: Authors' Affiliations: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands; and r.bernards@nki.nl w.zwart@nki.nl.
authors.forename: René
authors.initials: R
authors.lastname: Bernards
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D016000:Cluster Analysis; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D013629:Tamoxifen / Q000627:therapeutic use*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D002843:Chromatin; D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; C506234:USP9X protein, human; D013629:Tamoxifen; D043222:Ubiquitin Thiolesterase