AlphaB-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-crystallin (alphaB-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 alphaB-crystallin transformed immortalized human mammary epithelial cells (MECs). In 3D basement membrane culture, alphaB-crystallin overexpression induced luminal filling and other neoplastic-like changes in mammary acini, while silencing alphaB-crystallin by RNA interference inhibited these abnormalities. alphaB-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 alphaB-crystallin was suppressed by MEK inhibitors. In addition, immortalized human MECs overexpressing alphaB-crystallin formed invasive mammary carcinomas in nude mice that recapitulated aspects of human basal-like breast tumors. Collectively, our results indicate that alphaB-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.
Moyano
Jose V
JV
Cell Death Regulation Laboratory, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Evans
Joseph R
JR
Chen
Feng
F
Lu
Meiling
M
Werner
Michael E
ME
Yehiely
Fruma
F
Diaz
Leslie K
LK
Turbin
Dmitry
D
Karaca
Gamze
G
Wiley
Elizabeth
E
Nielsen
Torsten O
TO
Perou
Charles M
CM
Cryns
Vincent L
VL
D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics*; D011379:Prognosis; D034622:RNA Interference; D016019:Survival Analysis; D017211:Treatment Failure; D038203:alpha-Crystallin B Chain / Q000235:genetics*
D015513:Oncogene Proteins; D038203:alpha-Crystallin B Chain