MYB regulates the DNA damage response and components of the homology-directed repair pathway in human estrogen receptor-positive breast cancer cells

Abstract

Over 70% of human breast cancers are estrogen receptor-positive (ER+), most of which express MYB. In these and other cell types, the MYB transcription factor regulates the expression of many genes involved in cell proliferation, differentiation, tumorigenesis, and apoptosis. So far, no clear link has been established between MYB and the DNA damage response in breast cancer. Here, we found that silencing MYB in the ER+ breast cancer cell line MCF-7 led to increased DNA damage accumulation, as marked by increased γ-H2AX foci following induction of double-stranded breaks. We further found that this was likely mediated by decreased homologous recombination-mediated repair (HRR), since silencing MYB impaired the formation of RAD51 foci in response to DNA damage. Moreover, cells depleted for MYB exhibited reduced expression of several key genes involved in HRR including BRCA1, PALB2, and TOPBP1. Taken together, these data imply that MYB and its targets play an important role in the response of ER+ breast cancer cells to DNA damage, and suggest that induction of DNA damage along with inhibition of MYB activity could offer therapeutic benefits for ER+ breast cancer and possibly other cancer types.

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Acknowledgments

We would like to thank members of the Gonda laboratory for helpful discussions. RMY was the recipient of an International Postgraduate Research Scholarship (Australia) and a University of Queensland Centennial Scholarship. ED was supported by a National Breast Cancer Foundation Early Career Fellowship. KKK is a Senior Principal Research Fellow of the National Health and Medical Research Council (Australia). The Translational Research Institute is supported by an Australian government grant.

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Correspondence to Eloise Dray or Thomas J. Gonda.

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Yang, R., Nanayakkara, D., Kalimutho, M. et al. MYB regulates the DNA damage response and components of the homology-directed repair pathway in human estrogen receptor-positive breast cancer cells. Oncogene 38, 5239–5249 (2019). https://doi.org/10.1038/s41388-019-0789-3

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