NF-kB Complex Activation and Association of αB-Crystallin and Vimentin with Poor Prognosis in Primary Breast Cancer.

Abstract

Abstract Background: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a protein complex found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, free radicals, cytokines et.c. NF-kB plays a key role in regulating the immune response and incorrect regulation of NF-kB has been linked to the development of cancer, several inflammatory and autoimmune diseases. The role of NF-kB, its subunits and pathways in breast cancer and in the surrounding stromal tissues remains uncertain. αB-crystallin is a heat shock protein, which function as stress-induced molecular chaperones to inhibit the aggregation of denatured proteins. Previous studies have identified αB-crystallin as a marker of poor prognosis for breast cancer and have suggested that it is an excellent marker for tumours of basal origin. The aim of this study is to examine, for the first time, NF-kB and αB-crystallin, vimentin and HSPs in the same set of breast cancers and stroma and relate this to clinical parameters including outcome.Methods: Tissue Micro Arrays of 0.6mm cores of 246 breast cancers were stained with antibodies to αB-crystallin, vimentin, HSP27 (antibody ERD5) and HSP27 82P and 12 subsequent antibodies for NF-kB (IKKa, Ser276, Ser32/36, 180/181, P52, 1kkygmma, P65, RELB, P100/P52, IkBa, cREL, and P50) and scored using the Quick Score Method.Results: Positive associations have been found between αB-crystallin and IKBA (P=0.001 Fishers exact test (FET)), RELB (P<0.001 (FET)) and SER32/36 (P=0.03 (FET)) whereas Vimentin was positively associated IKBA (P=0.003 (FET)), IKKA (P=0.001 (FET)), P50 (P=0.002 (FET)), RELB (P<0.001 (FET)) and SER32/36 (P=0.01 (FET)). Positive associations have also been found between HSP27 and P50 (P=0.002 (FET)), SER32/36 (P<0.001 (FET)). Antibodies such as 180/181 (P=0.04 Kaplan Meier Log Rank (KM), cREL (P=0.03 (KM)), IKBA (P=0.03 (KM)) and IKKA (P=0.01 (KM)) was associated with good survival and P50 (P=0.002 (KM)) and P65 (P=0.01 (KM)) to poor survival. Expression of αB-crystallin was associated with vimentin (P<0.001 (FET)). Its expression was linked to a low expression of the estrogen receptor. Vimentin expression was associated with estrogen receptor (ER) negative cancers and poor survival (P <0.001 (FET)), P=0.002 (KM Log Rank) respectively). In contrast to αB-crystallin, low expression of HSP27 was associated with low ER and progesterone receptor (PGR).Conclusions: Associations were found between various antibodies within the NF-kB pathway as well as the heat shock proteins αB-crystallin, vimentin and HSP27 with varying implications for overall survival. We aim to clarify the mechanisms to prevent the aggregation of stress-accumulated misfolded proteins and apoptosis resulting better survival. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2143.