USP9X Downregulation Renders Breast Cancer Cells Resistant to Tamoxifen

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-07, Vol.74 (14), p.3810-3820
• Main Authors: OOSTERKAMP, Hendrika M, HIJMANS, E. Marielle, BRUMMELKAMP, Thijn R, CANISIUS, Sander, WESSELS, Lodewyk F. A, ZWART, Wilbert, BERNARDS, René
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents, Hormonal - therapeutic use; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Cell Line, Tumor; Chromatin - metabolism; Cluster Analysis; Down-Regulation; Drug Resistance, Neoplasm - genetics; Estrogen Receptor alpha - metabolism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; Protein Binding; RNA, Small Interfering - genetics; Tamoxifen - therapeutic use; Tumors; Ubiquitin Thiolesterase - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-1960

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.