Data from DDX5 Regulates DNA Replication and Is Required for Cell Proliferation in a Subset of Breast Cancer Cells

Abstract

<div>Abstract<p>Understanding factors required for DNA replication will enrich our knowledge of this important process and potentially identify vulnerabilities that can be exploited in cancer therapy. We applied an assay that measures the stability of maintenance of an episomal plasmid in human tissue culture cells to screen for new DNA replication factors. We identify an important role for DDX5 in G<sub>1</sub>–S-phase progression where it directly regulates DNA replication factor expression by promoting the recruitment of RNA polymerase II to E2F-regulated gene promoters. We find that the <i>DDX5</i> locus is frequently amplified in breast cancer and that breast cancer–derived cells with amplification of <i>DDX5</i> are much more sensitive to its depletion than breast cancer cells and a breast epithelial cell line that lacks DDX5 amplification. Our results show a novel role for <i>DDX5</i> in cancer cell proliferation and suggest DDX5 as a therapeutic target in breast cancer treatment.</p><p><b>Significance:</b> DDX5 is required for cell proliferation by controlling the transcription of genes expressing DNA replication proteins in cancer cells in which the <i>DDX5</i> locus is amplified, and this has uncovered a dependence on DDX5 for cell proliferation. Given the high frequency of <i>DDX5</i> amplification in breast cancer, our results highlight DDX5 as a promising candidate for targeted therapy of breast tumors with <i>DDX5</i> amplification, and indeed we show that DDX5 inhibition sensitizes a subset of breast cancer cells to trastuzumab. <i>Cancer Discov; 2(9); 812–25. ©2012 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 753.</p></div>