%0 Journal Article
%T Effects of clusterin over-expression on metastatic progression and therapy in breast cancer
%A Louise Flanagan
%A Lorna Whyte
%A Namita Chatterjee
%A Martin Tenniswood
%J BMC Cancer
%D 2010
%I BioMed Central
%R 10.1186/1471-2407-10-107
%X To 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.In 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.These 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.The development of a metastatic, hormone-independent and drug resistant phenotype is responsible for a high percentage of treatment failures among breast cancer patients. Therefore, understanding the molecular mechanisms of metastasis is crucial for the design and effective use of novel therapeutic strategies to combat tumor progression [1-3]. Whether the phenotypes of drug resistance, hormone independence and invasion are linked genotypically, or whether they involve independent genetic or epigenetics processes, remains to be determined. Clusterin is a secreted heterodimeric 70-80 kDa glycoprotein composed of alpha and beta chains linked by fiv
%U http://www.biomedcentral.com/1471-2407/10/107