The Role of Osteopontin in the Malignancy of Human Breast Carcinoma
Final rept. 1 Jun 96-31 May 99
VICTORIA HOSPITAL CORP LONDON (ONTARIO) RESEARCH INST
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The objective of this research is to establish whether the secreted phosphoprotein osteopontin OPN plays a biological role in the progression of breast carcinoma cells, and to determine the nature of this role, by asking if cell properties and genes associated with malignancy are regulated by OPN. This work makes use of three established mammaryepithelial cell lines 21T series derived from the same patient 2lPT cells are immortal but nontumorigenic in the nude mouse 21NT are weakly tumorigenic, but non-metastatic and 21 MT-1 are tumorigenic, weakly metastatic. In addition, MDA-MB-435 cells are included, representative of a highly malignant, metastatic cell line. We have found that OPN mRNA and protein expression is associated with degree of malignancy in this progression series. Further, we have shown that the more malignant members of this series also bind better OPN in cell adhesion assays. 2lT series and MDA-MBA35 cells have all demonstrated directed migration towards exogenous OPN, and this was associated with increased expression of Met HOF receptor mRNA increased Met activity and increased sensitivity to HGF. We have found that cell adhesion and migration of 21 T series and MDA-MB-435 cells are mediated via cell surface integrins, with involvement of CD44 as well. Interestingly, MDA-MB435 cells show alphavBeta5 integrin-dependent cell adhesion and migration, whereas 2lT series cells exclusively use alphavBeta51 and Beta1 integrins. In cell invasion assays, MDA-MBA35 cells showed a more pronounced response to exogenous OPN than 21PT or 2lNT cells.
- Anatomy and Physiology
- Medicine and Medical Research