1410

CRYAB

crystallin, alpha B;CRYAB;crystallin, alpha B

alpha-crystallin B chain|epididymis secretory protein Li 101|heat shock protein beta-5|heat-shock 20 kD like-protein|renal carcinoma antigen NY-REN-27|rosenthal fiber component

11q22.3-q23.1

protein-coding

AIM: Alpha B-Crystallin (CRYAB) is purported to be a metastasis suppressor protein, and lack or lower CRYAB expression is a prognostic biomarker for several types of cancer, such as that of the prostate and head and neck. However, the association of genomic variation of CRYAB and breast cancer is not well studied. The aim of this study was to evaluate the association of polymorphic genotypes of CRYAB with breast cancer within a Taiwanese population. PATIENTS AND METHODS: In this hospital-based study, 1232 patients with breast cancer and an equal number of healthy controls in central Taiwan were genotyped via polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) and the association of CRYAB A-1215G (rs2228387), C-802G (rs14133) and intron 2 (rs2070894) polymorphisms with breast cancer risk in a central Taiwanese population was investigated. RESULTS: Those individuals with CRYAB C-802G CG and GG genotypes had 1.50- and 2.22-fold risk for breast cancer than those with the CC genotype. As for the A-1215G and intron 2 polymorphisms, there was no significant association of the genotype with breast cancer risk. In allelic frequency analysis, the G allele CRYAB C-802G conferred a significantly (p=5.63x10(-10)) increased risk of breast cancer. Our results provide evidence that the G allele of CRYAB C-802G is correlated with breast cancer risk and this polymorphism may be a useful marker for early detection of breast cancer in clinical practice.

PURPOSE: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone alphaB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of alphaB-crystallin in brain metastasis in TNBCs. EXPERIMENTAL DESIGN: alphaB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. alphaB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood-brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing alphaB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models. RESULTS: In a cohort of women with breast cancer brain metastasis, alphaB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of alphaB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing alphaB-crystallin inhibited these events. alphaB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an alpha3beta1 integrin-dependent mechanism. alphaB-crystallin overexpression promoted brain metastasis, whereas silencing alphaB-crystallin inhibited brain metastasis in orthotopic TNBC models. CONCLUSION: alphaB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease.

AIM: Alpha B-Crystallin (CRYAB) is purported to be a metastasis suppressor protein, and lack or lower CRYAB expression is a prognostic biomarker for several types of cancer, such as that of the prostate and head and neck. However, the association of genomic variation of CRYAB and breast cancer is not well studied. The aim of this study was to evaluate the association of polymorphic genotypes of CRYAB with breast cancer within a Taiwanese population. PATIENTS AND METHODS: In this hospital-based study, 1232 patients with breast cancer and an equal number of healthy controls in central Taiwan were genotyped via polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) and the association of CRYAB A-1215G (rs2228387), C-802G (rs14133) and intron 2 (rs2070894) polymorphisms with breast cancer risk in a central Taiwanese population was investigated. RESULTS: Those individuals with CRYAB C-802G CG and GG genotypes had 1.50- and 2.22-fold risk for breast cancer than those with the CC genotype. As for the A-1215G and intron 2 polymorphisms, there was no significant association of the genotype with breast cancer risk. In allelic frequency analysis, the G allele CRYAB C-802G conferred a significantly (p=5.63x10(-10)) increased risk of breast cancer. Our results provide evidence that the G allele of CRYAB C-802G is correlated with breast cancer risk and this polymorphism may be a useful marker for early detection of breast cancer in clinical practice.