In a study of ductal carcinoma in situ of the breast, we identified five genes at chromosome 17q21.33 that were over-expressed in high grade cases, and showed a correlation between expression and gene copy number. The aim of this study was to investigate potential drivers of genomic amplification at 17q21.33. Analysis of high resolution comparative genomic hybridisation and published data specified a minimum region of amplification at 17q21.33. Prohibitin (PHB) expression was examined by immunohistochemistry in 285 invasive breast cancers. Gene copy number was examined by fluorescence in situ hybridisation. The minimum region of amplification at 17q21.33 included ten genes with PHB selected as a candidate driver. Increased PHB expression was associated with higher grade breast cancer and poorer survival. Amplification of PHB was detected in 13 of 235 cases (5.5%) but was not associated with PHB expression. PHB amplification was most common in the ERBB2+ breast cancer subtype, although high expression was most prevalent in basal-like and luminal B cancers. Amplification at 17q21.33 is a recurrent feature of breast cancer that forms part of a ‘firestorm’ pattern of genomic aberration. PHB is not a driver of amplification, however PHB may contribute to high grade breast cancer.