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Breast Cancer Research and Treatment

, Volume 146, Issue 2, pp 287–297

First Online: 15 June 2014Received: 04 November 2013Accepted: 31 May 2014DOI: 10.1007-s10549-014-3019-2

Cite this article as: Varley, K.E., Gertz, J., Roberts, B.S. et al. Breast Cancer Res Treat 2014 146: 287. doi:10.1007-s10549-014-3019-2

Abstract

Read-through fusion transcripts that result from the splicing of two adjacent genes in the same coding orientation are a recently discovered type of chimeric RNA. We sought to determine if read-through fusion transcripts exist in breast cancer. We performed paired-end RNA-seq of 168 breast samples, including 28 breast cancer cell lines, 42 triple negative breast cancer primary tumors, 42 estrogen receptor positive ER+ breast cancer primary tumors, and 56 non-malignant breast tissue samples. We analyzed the sequencing data to identify breast cancer associated read-through fusion transcripts. We discovered two recurrent read-through fusion transcripts that were identified in breast cancer cell lines, confirmed across breast cancer primary tumors, and were not detected in normal tissues SCNN1A-TNFRSF1A and CTSD-IFITM10. Both fusion transcripts use canonical splice sites to join the last splice donor of the 5′ gene to the first splice acceptor of the 3′ gene, creating an in-frame fusion transcript. Western blots indicated that the fusion transcripts are translated into fusion proteins in breast cancer cells. Custom small interfering RNAs targeting the CTSD-IFITM10 fusion junction reduced expression of the fusion transcript and reduced breast cancer cell proliferation. Read-through fusion transcripts between adjacent genes with different biochemical functions represent a new type of recurrent molecular defect in breast cancer that warrant further investigation as potential biomarkers and therapeutic targets. Both breast cancer associated fusion transcripts identified in this study involve membrane proteins SCNN1A-TNFRSF1A and CTSD-IFITM10, which raises the possibility that they could be breast cancer-specific cell surface markers.

Electronic supplementary materialThe online version of this article doi:10.1007-s10549-014-3019-2 contains supplementary material, which is available to authorized users.

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