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. 2009 Feb 5;28(5):742-51.
doi: 10.1038/onc.2008.430. Epub 2008 Dec 1.

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

A R Thorner  1 , K A Hoadley, J S Parker, S Winkel, R C Millikan, C M Perou
Affiliations

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

A R Thorner et al. Oncogene. .

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 IIalpha 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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Figures

Figure 1
Figure 1. B-Myb expression across breast cancer subtypes
The NKI breast tumor microarray dataset (n=295) was classified into the five intrinsic subtypes and box plots used to visualize B-Myb expression according to breast cancer subtypes. Statistical significance was calculated by ANOVA.
Figure 2
Figure 2. High expression of B-Myb correlates with poor outcome
Kaplan-Meier survival analyses based on B-Myb expression values rank ordered into halves (low/high). (A-D) Overall survival (OS) of locally treated NKI tumor samples: (A) All subtypes combined (n=165), (B) Luminal A (n=72), (C) Luminal B (n=26), (D) HER2+/ER− (n=21). (E) RFS, Wang et al., 2005 (n=286), a locally treated, lymph-node-negative tumor microarray dataset. (F) Miller et al., 2005 breast tumor microarray dataset (n=234).
Figure 3
Figure 3. Drug sensitivities in B-Myb overexpressing cell lines
IC50 doses (72h) of chemotherapy on cell lines stably expressing vector control, B-Myb, or B-Myb S427G variant. Each MTT experiment was performed in triplicate and error bars represent 95% confidence intervals (*p<0.001 relative to vector control). (A) hTERT-immortalized HMEC line HME-CC. (B) hTERT-immortalized HMEC line ME16C. (C) Basal-like tumor derived cell line SUM102 and (D) SUM149.
Figure 4
Figure 4. Enrichment of G2/M phase genes in doxorubicin-treated B-Myb overexpressing HME-CC cells
Significance Analysis of Microarray was used to identify 217 significant genes whose high expression was present in B-Myb overexpressing cells. These genes were then assigned to a specific phase of the cell cycle by comparing them to Whitfield et al., 2002, which identified 101/217 genes as being specifically induced during the cell cycle. The graph shows to which phase of the cell cycle these 101 genes mapped.
Figure 5
Figure 5. Cell cycle profile of HME-CC cells stably expressing B-Myb and treated with doxorubicin
Cell cultures were treated with a range of doses of doxorubicin for 48 hours followed by propidium iodide DNA content analysis. Percentage of cells in (A) G1 phase and (B) G2/M were calculated by gating based on DNA content. Error bars indicate standard deviations between three independent experiments.
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