Gene-expression profiling is an important tool for classifying cancers into subgroups with prognostic significance. However, not much is known about how most of the individual genes in these signatures contribute to their associated clinical phenotypes. Jose Moyano et al. have linked α-basic crystallin (αB-crystallin), a stress-response protein with oncogenic potential, to an aggressive subtype of human breast tumours (basal-like) identified by gene profiling.

The basal-like group of breast tumours is oestrogen receptor-negative and ERBB2-negative, and is associated with short overall and relapse-free survival times, but little is known about how the genes expressed by this tumour type lead to its aggressive behaviour. Moyano et al. examined existing breast cancer microarray data and noticed that αB-crystallin, a cell stress protein of long-standing interest to their laboratory, was frequently expressed in this tumour type.

αB-crystallin is a member of the small-heat-shock-protein (HSP) family. These proteins function as stress-induced molecular chaperones that promote cell survival. Ectopic expression of αB-crystallin protects cells against a broad range of apoptotic stimuli, whereas silencing of its expression with RNA interference (RNAi) sensitizes cells to apoptosis. αB-crystallin is also highly expressed in gliomas, prostate tumours and renal-cell carcinoma, so Moyano et al. explored its potential function in basal-like breast tumours.

They observed that αB-crystallin was expressed in about half of basal-like breast tumour samples, and its expression could predict shorter survival times in patients independently of other established markers. Overexpression of the wild-type protein, but not a pseudophosphorylation mutant, induced neoplastic changes in mammary acini growth in three-dimensional culture systems and transformed immortalized human mammary epithelial cells. These cells underwent anchorage-independent proliferation, became highly migratory and invasive in vitro and formed invasive mammary carcinomas in nude mice. Studies with the pseudophosphorylation mutant indicated that the oncogenic activity of αB-crystallin is negatively regulated by phosphorylation.

How does αB-crystallin transform mammary epithelial cells? The authors found that overexpression of αB-crystallin increased levels of total and phosphorylated extracellular-regulated kinase 1 (ERK1)/ERK2 proteins, activating the ERK–MEK (mitogen-activated protein kinase (MAPK) kinase) signalling pathway. This activation is required for transformation — treatment of the cells with MEK inhibitors suppressed their malignant phenotype. As αB-crystallin is a molecular chaperone, the authors propose that it could regulate ERK1/ERK2 stability or phosphorylation, much as HSP90 regulates the activity of the kinases AKT and RAF.

The authors are examining the expression of αB-crystallin in additional breast cancer cohorts to see if its expression level could be a useful marker of prognosis or drug response. Furthermore, these findings indicate that the MEK inhibitors, which are already in clinical trials for the treatment of other cancer types, might be used to treat patients with basal-like breast tumours.