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In vitro and in vivo analysis of B-Myb in basal-like breast cancer

Oncogene volume 28, pages 742–751 (2009)Cite this article

Abstract

A defining feature of basal-like breast cancer, a breast cancer subtype with poor clinical prognosis, is the high expression of ‘proliferation signature’ genes. We identified B-Myb, a MYB family transcription factor that is often amplified and overexpressed in many tumor types, as being highly expressed in the proliferation signature. However, the roles of B-Myb in disease progression, and its mammary-specific transcriptional targets, are poorly understood. Here, we showed that B-Myb expression is a significant predictor of survival and pathological complete response to neoadjuvant chemotherapy in breast cancer patients. We also identified a significant association between the G/G genotype of a nonsynonymous B-Myb germline variant (rs2070235, S427G) and an increased risk of basal-like breast cancer [OR 2.0, 95% CI (1.1–3.8)]. In immortalized, human mammary epithelial cell lines, but not in basal-like tumor lines, cells ectopically expressing wild-type B-Myb or the S427G variant showed increased sensitivity to two DNA topoisomerase IIα inhibitors, but not to other chemotherapeutics. In addition, microarray analyses identified many G2/M genes as being induced in B-Myb overexpressing cells. These results confirm that B-Myb is involved in cell cycle control, and that its dysregulation may contribute to increased sensitivity to a specific class of chemotherapeutic agents. These data provide insight into the influence of B-Myb in human breast cancer, which is of potential clinical importance for determining disease risk and for guiding treatment.

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Acknowledgements

We thank Drs Melissa A Troester and William K Kaufmann for comments and discussion. This work was supported by funds from the NCI Breast SPORE program (P50-CA58223-09A1), by RO1-CA-101227-01, by the Breast Cancer Research Foundation and the V Foundation for Cancer Research.

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Authors and Affiliations

  1. Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC, USA

    A R Thorner

  2. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    A R Thorner, K A Hoadley & C M Perou

  3. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    A R Thorner, K A Hoadley, J S Parker, S Winkel, R C Millikan & C M Perou

  4. Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA

    S Winkel & R C Millikan

  5. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA

    C M Perou

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Correspondence to C M Perou.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Thorner, A., Hoadley, K., Parker, J. et al. In vitro and in vivo analysis of B-Myb in basal-like breast cancer. Oncogene 28, 742–751 (2009). https://doi.org/10.1038/onc.2008.430

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