Effects of clusterin over-expression on metastatic progression and therapy in breast cancer

Abstract

BackgroundClusterin is a secreted glycoprotein that is upregulated in a variety of cell lines in response to stress, and enhances cell survival. A second nuclear isoform of clusterin that is associated with cell death has also been identified. The aim of this study was to determine the role(s) of the secretory isoform in breast tumor progression and metastasis.MethodsTo investigate the role of secretory clusterin in the biology of breast cancer tumor growth and resistance to therapy we have engineered an MCF-7 cell line (MCF-7CLU) that over-expresses clusterin. We have measured the in vitro effects of clusterin over-expression on cell cycle, cell death, and sensitivity to TNFalpha and tamoxifen. Using an orthotopic model of breast cancer, we have also determined the effects of over-expression of clusterin on tumor growth and metastatic progression.ResultsIn vitro, over-expression of secretory clusterin alters the cell cycle kinetics and decreases the rate of cell death, resulting in the enhancement of cell growth. Over-expression of secretory clusterin also blocks the TNFalpha-mediated induction of p21 and abrogates the cleavage of Bax to t-Bax, rendering the MCF-7CLU cells significantly more resistant to the cytokine than the parental cells. Orthotopic primary tumors derived from MCF-7CLU cells grow significantly more rapidly than tumors derived from parental MCF-7 cells and, unlike the parental cells, metastasize frequently to the lungs.ConclusionsThese data suggest that secretory clusterin, which is frequently up-regulated in breast cancers by common therapies, including anti-estrogens, may play a significant role in tumor growth, metastatic progression and subsequent drug resistance in surviving cells.

Clusterin Mediates TGF-β–Induced Epithelial–Mesenchymal Transition and Metastasis via Twist1 in Prostate Cancer Cells

“…Similarly, CLU overexpression in hepatocellular carcinoma increased migratory and metastatic abilities in vitro and in vivo (17). Recently, orthotopic primary tumors derived from CLU-overexpressing breast cancer cells grew more rapidly and metastasized more often than tumors derived from parental cells (43). Collectively, these findings link CLU overexpression to promotion of metastases in several types of cancer.…”

Diagnostic and prognostic significance of secretory clusterin expression in patients with hepatocellular carcinoma

“…Furthermore, univariate and multivariate analyses indicated that sCLU might be an independent prognostic indicator, in line with the factor of lymph node metastasis. In fact, associations between CLU overexpression and metastasis have been revealed by considerable evidence [31][32][33], and recent studies suggest that abnormal sCLU expression could contribute to metastasis in human HCC [34].…”

Prognostic impact of polymorphisms in the MYBL2 interacting genes in breast cancer

“…The CLU promoter SNP, rs9331888 was associated with positive regional lymph node metastasis and high stage. Expression of CLU has been related to tumourigenesis and progression as well as poor prognosis in BC [14,15,30]. Some studies on the polymorphisms in CLU [31,32] have been published, but none of them in BC or other cancers.…”

“…E2F1, E2F3 and E2F4 have been suggested to contribute to the prognosis for BC by previous studies [11]. Several MYBL2 regulated genes have been identified as prognostic factors for BC, including BCL2 [12], BIRC5 [13], CLU [14,15], ERBB2 [16] and TOP2A [17].…”