Differential Gene Expression in Tamoxifen-Resistant Breast Cancer Cells Revealed by a New Analytical Model of RNA-Seq Data

Kathryn J. Huber-Keener, Xiuping Liu, Zhong Wang, Yaqun Wang, Willard Freeman, Song Wu, Maricarmen D. Planas-Silva, Xingcong Ren, Yan Cheng, Yi Zhang, Kent Vrana, Chang-Gong Liu, Jin-Ming Yang, Rongling Wu

Resistance to tamoxifen (Tam), a widely used antagonist of the estrogen receptor (ER), is a common obstacle to successful breast cancer treatment. While adjuvant therapy with Tam has been shown to significantly decrease the rate of disease recurrence and mortality, recurrent disease occurs in one third of patients treated with Tam within 5 years of therapy. A better understanding of gene expression alterations associated with Tam resistance will facilitate circumventing this problem. Using a next generation sequencing approach and a new bioinformatics model, we compared the transcriptomes of Tam-sensitive and Tam-resistant breast cancer cells for identification of genes involved in the development of Tam resistance. We identified differential expression of 1215 mRNA and 513 small RNA transcripts clustered into ERα functions, cell cycle regulation, transcription/translation, and mitochondrial dysfunction. The extent of alterations found at multiple levels of gene regulation highlights the ability of the Tam-resistant cells to modulate global gene expression. Alterations of small nucleolar RNA, oxidative phosphorylation, and proliferation processes in Tam-resistant cells present areas for diagnostic and therapeutic tool development for combating resistance to this anti-estrogen agent.