Molecular Mechanisms of Metastatic Progression in Breast Cancer
Abstract
Clusterin is a multifunctional disulphide linked protein that is induced during regression of hormone dependent tissues. of particular interest to us is the observation that clusterin expression is confined to surviving cells following induction of cell death, suggesting that it may be involved in cell survival rather than cell death. Clusterin expression has also been correlated with tumor grade and resistance to cytotoxic compounds such as TNF-alpha in prostate cancer. In our studies we have focused on determining whether clusterin plays a causative role in the progression of human breast carcinoma by promoting cell survival, increasing cell motility and resistance to cytotoxic drugs. Our studies have utilized an ER-alpha positive non-invasive MCF-7 cell line, an MCF-7 cell line genetically engineered to overexpress clusterin (MCF- 7CLU) and an ER-alpha negative invasive SUM-159PT cell line. Our major finding to date are that SUM-159PT and MCF- 7CLU cells secrete 5-10 times more clusterin than MCF-7 cells. Both SUM-159PT and MCF-7CLU cells display resistance to TNF-alpha in comparison to the highly sensitive MCF-7 cells. Furthermore, our in vitro invasion assays demonstrate a dramatic increase (10 fold) in the invasive potential of the MCF-7CLU cells as compared to the parental non-invasive MCF-7 cells. Our data clearly demonstrate a role for clusterin in breast tumor promotion and resistance to possible thereapeutic compounds. In vivo studies currently underway are focusing on tumor growth and progression in the MCF-7 vs MCF-7CLU cell lines, followed by measuring sensitivity to the most commonly used clinical antiestrogen tamoxifen.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA418756
Entities
People
- Louise A. Flanagan
Organizations
- University of Notre Dame