8p21.1

AAG4,APO-J,APOJ,CLI,CLU1,CLU2,KUB1,NA1/NA2,SGP-2,SGP2,SP-40,TRPM-2,TRPM2

Prostate cancer

Several studies have shown decreased clusterin levels in prostate cancer (Bettuzzi et al., 2000; Scaltriti et al., 2004; Rauhala et al., 2008). On the other hand, there are also reports on increased expression of clusterin in prostate cancer, specifically after androgen ablation therapy (July et al., 2002). These opposing results have been explained by the different isoforms of clusterin, i.e. proapoptotic nCLU being decreased, while antiapoptotic, pro-survival sCLU could be increased. Antisense oligonucleotide (ASO) therapy against clusterin is currently tested in clinical trials to evaluate its efficacy in improving androgen deprivation therapy, as well as to prevent chemoresistance (reviewed in Gleave and Miyake, 2005; Sowery et al., 2008). Data supporting the tumor suppressive role for clusterin include reports on epigenetic regulation of clusterin expression in prostate cancer cell lines (Rauhala et al., 2008) and a recently developed TRAMP/cluKO mouse clusterin knock-out model that develops more poorly differentiated and metastatic tumors (Bettuzzi et al., 2008).

Breast cancer

Clusterin expression has been shown to increase in breast cancer (Redondo et al., 2000; Kruger et al., 2007). Similarly to prostate cancer, clusterin ASO therapy is being tested also for breast cancer. Recent results from phase II trial did not support show significant increase in treatment response when docetaxel was combined with anti-clusterin therapy (Chia et al., 2009).

Ovarian cancer

Cytoplasmic clusterin expression has been shown to increase in ovarian cancer in stage-specific manner and in response to chemotherapy as a cell-survival promoter (Xie et al., 2007; Wei et al., 2009).

Colorectal cancer

Increased cytoplasmic clusterin expression has also been found in colorectal cancers (Xie et al., 2005), and the increased clusterin levels were shown to associate with poor prognosis of stage II colon cancers (Kevans et al., 2009). Clusterin has also been suggested to be a potential stool biomarker for colon cancer screening (Pucci et al., 2009).

Pancreatic cancer

In pancreatic cancer the reports of clusterin expression are controversial, with both high and low expression reported for cancers (Xie et al., 2002; Jhala et al., 2006). Lack of clusterin expression was also suggested as a potential discriminator factor for distinguishing pancreatic adenocarcinomas from pancreatic patients from fine-needle aspirations (Jhala et al., 2006). In pancreatic cancers, clusterin expression was associated with longer survival, supporting the idea of clusterin down-regulation in tumor progression (Xie et al., 2002).

Alzheimers disease

Increased clusterin levels are shown in Alzheimers disease, mostly in astrocytes. Clusterin can bind to amyloid-beta peptides stabilizing them leading to their clearance from the brain. Fibrillized amyloid deposits can be masked by clusterin so that they are not recognized by the host defense system, thus preventing excessive inflammation reaction. Additional protection of neural cells is achieved by inhibiting the complement activation. Furthermore, clusterin can function antiapoptotically through Bax-interference and potentiate survival mediated through TGF-beta signaling. (Reviewed in Nuutinen et al., 2009).

Nephrotic syndrome

Clusterin expression is decreased in glomerular diseases causing nephrotic syndrome, with hypercholesterolemia appearing as the unifying feature (Ghiggeri et al., 2002).