In vitro and in vivo analysis of B-Myb in basal-like breast cancer.
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.
Thorner
A R
AR
Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
Hoadley
K A
KA
Parker
J S
JS
Winkel
S
S
Millikan
R C
RC
Perou
C M
CM
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D002280:Basal Cell Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis; D059005:Topoisomerase II Inhibitors; D015534:Trans-Activators / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C064352:MYBL2 protein, human; D059005:Topoisomerase II Inhibitors; D015534:Trans-Activators; D004250:DNA Topoisomerases, Type II