αB-Crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer
Jose V. Moyano, … , Charles M. Perou, Vincent L. Cryns
Jose V. Moyano, … , Charles M. Perou, Vincent L. Cryns
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):261-270. https://doi.org/10.1172/JCI25888.
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Categories: Research Article Oncology

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

Abstract

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 α-basic–crystallin (αB-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 αB-crystallin transformed immortalized human mammary epithelial cells (MECs). In 3D basement membrane culture, αB-crystallin overexpression induced luminal filling and other neoplastic-like changes in mammary acini, while silencing αB-crystallin by RNA interference inhibited these abnormalities. αB-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 αB-crystallin was suppressed by MEK inhibitors. In addition, immortalized human MECs overexpressing αB-crystallin formed invasive mammary carcinomas in nude mice that recapitulated aspects of human basal-like breast tumors. Collectively, our results indicate that αB-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.

Authors

Jose V. Moyano, Joseph R. Evans, Feng Chen, Meiling Lu, Michael E. Werner, Fruma Yehiely, Leslie K. Diaz, Dmitry Turbin, Gamze Karaca, Elizabeth Wiley, Torsten O. Nielsen, Charles M. Perou, Vincent L. Cryns

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Figure 1

αB-Crystallin is expressed in the basal-like subtype of breast cancer and independently predicts shorter survival.

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αB-Crystallin is expressed in the basal-like subtype of breast cancer an...
(A) Expanded view of the basal epithelial gene expression cluster presented by Sorlie et al. (4) (red, above average gene expression; green, below average gene expression; black, average gene expression). (B) αB-Crystallin and (C) CK5/6 expression by IHC in the same breast carcinoma that shows a basal-like gene expression and IHC profile. (D) Representative immunostaining of normal human breast tissue for αB-crystallin expression. (E) αB-Crystallin IHC of 3 representative breast carcinomas in the TMA study: strongly positive (left), weakly positive (middle), and negative (right) examples are shown. (F) Kaplan-Meier survival analysis of breast cancer–specific survival based on αB-crystallin expression. Invasive breast carcinomas were scored as positive or negative for αB-crystallin expression (left), or αB-crystallin staining was graded as weakly positive or strongly positive (right). Original magnification, ×100 (B–D), ×200 (E).