Cancer Research The Future of Cancer Research: Science and Patient Impact AACR Conference on Molecular Diagnostics - 2008
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[Cancer Research 60, 3359-3363, July 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Down-Regulation of HP1Hs{alpha} Expression Is Associated with the Metastatic Phenotype in Breast Cancer1

Dawn A. Kirschmann2, Ruth A. Lininger, Lynn M. G. Gardner, Elisabeth A. Seftor, Valerie A. Odero, Alexandra M. Ainsztein3, William C. Earnshaw, Lori L. Wallrath and Mary J. C. Hendrix

Departments of Anatomy and Cell Biology [D. A. K., L. M. G. G., E. A. S., V. A. O., M. J. C. H.] and Biochemistry [L. L. W.], College of Medicine, University of Iowa Cancer Center, University of Iowa, Iowa City, Iowa 52242-1109; Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27514-7525 [R. A. L.]; and Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh Scotland, United Kingdom EH9 3JR [A. M. A., W. C. E.]

We previously identified a down-regulation in heterochromatin-associated protein 1 (HP1)Hs{alpha} expression in MDA-MB-231 breast carcinoma cells (highly invasive/metastatic) compared with MCF-7 cells (poorly invasive/nonmetastatic). In this study, we demonstrate that HP1Hs{alpha}, but not HP1Hsß or HP1Hs{gamma}, is down-regulated at the mRNA and protein levels in highly invasive/metastatic breast cancer cell lines. In agreement, little to no nuclear HP1Hs{alpha} staining was observed in these cell lines. In contrast, poorly invasive/nonmetastatic cell lines showed HP1Hs{alpha} localization to the nucleus and nuclear membrane. Transfection of MDA-MB-231 cells with a green fluorescent protein-HP1Hs{alpha} expression vector decreased their ability to invade a collagen IV/laminin/gelatin matrix compared with green fluorescent protein-transfected controls. Consistent with the cell culture studies, immunohistochemical analysis of HP1Hs{alpha} protein localization in distant metastatic tissues from breast cancer patients revealed a decrease in the staining intensity and percentage of cells expressing HP1Hs{alpha} in seven of nine distant metastatic lesions compared with normal mammary and primary tumors. These results demonstrate a role for HP1Hs{alpha} in breast cancer invasion and metastasis. Given the role of HP1 in transcriptional silencing in Drosophila, we propose a model in which HP1Hs{alpha} normally silences genes involved in breast cancer invasion and metastasis.




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