YBX1 oncogene amplification and over-expression in breast cancer

Abstract

Breast cancer is a common diagnosis, however prognosis remains poor for certain subsets of patients and further understanding of breast cancer biology is sorely needed to identify new targets for therapy. The multifunctional YB-1 protein plays an important role in all the hallmarks of cancer and recent work has discovered amplification of the YBX1 gene encoding YB-1 in breast tumours. I aimed to identify the frequency of YBX1 amplification in breast cancers, to describe the common clinical characteristics of these tumours, to describe the region of amplification that contains the YBX1 gene, and to identify potential genes promoting amplification at this location. Genomic changes that occur in the setting of YBX1 amplification or over-expression, and whether circulating YBX1 or YB-1 is detectable in plasma, were also examined. Two datasets were used for this analysis and include results for almost 2000 invasive breast carcinomas. Several patient plasma samples were used to measure circulating YBX1 RNA and YB-1 protein. The presence of YBX1 amplification was rare but was found more frequently in patients with aggressive, grade 3 tumours. 12.8% of triple receptor negative cancers contained YBX1 amplification. Tumour YBX1 amplification commonly results in elevated YBX1 RNA expression; elevated YBX1 RNA expression was shown to result in poorer patient outcomes and gene amplification was also suggestive of poorer survival. YBX1 was co-amplified along with several genes. CDC20 and CTPS1 are two other co-located genes that may be promoting amplification on chromosome 1. YBX1 expression and amplification is associated with genomic changes at sites distal to 1p34, with loss of genes encoding proteins involved in DNA repair mechanisms on the long arm of chromosome 5 being a notable example. Both YBX1 RNA and YB-1 protein are detectable in small volumes of patient plasma, and a trend of reducing plasma YBX1 RNA level was observed in the plasma of patients whose primary tumours had lower log2 expression of YBX1 RNA. These findings more clearly define the population likely to benefit from any YB-1 targeted therapies, and suggest further research avenues to investigate the role of circulating biomarkers in the diagnosis of tumour YBX1 amplification.