αB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer

Recent gene profiling studies have identified a new breast cancer subtype, the basal-like group, which expresses genes characteristic of basal epithelial cells and is associated with poor clinical outcomes. However, the genes responsible for the aggressive behavior observed in this group are largely unknown. Here we report that the small heat shock protein alpha-basic-crystaflin (alpha B-crystallin) was commonly expressed in basal-like tumors and predicted poor survival in breast cancer patients independently of other prognostic markers. We also demonstrate that overexpression of aB-crystallin transformed immortalized human mammary epithelial cells (MECs). In 3D basement membrane culture, alpha B-crystallin overexpression induced luminal filling and other neoplastic-like changes in mammary acini, while silencing all-crystallin by RNA interference inhibited these abnormalities. alpha B-Crystallin overexpression also induced EGF- and anchorage-independent growth, increased cell migration and invasion, and constitutively activated the MAPK kinase/ERK (MEK/ERK) pathway. Moreover, the transformed phenotype conferred by alpha B-crystallin was suppressed by MEK inhibitors. In addition, immortalized human MECs overexpressing alpha B-crystallin formed invasive mammary carcinomas in nude mice that recapitulated aspects of human basal-like breast tumors. Collectively, our results indicate that alpha B-crystallin is a novel oncoprotein expressed in basal-like breast carcinomas that independently predicts shorter survival. Our data also implicate the MEK/ERK pathway as a potential therapeutic target for these tumors.