Down-regulation of HP1(Hs alpha) expression is associated with the metastatic phenotype in breast cancer

We previously identified a down regulation in heterochromatin-associated pr otein 1 (HP1)(Hs alpha) expression in MDA-MB-231 breast carcinoma cells (hi ghly invasive/metastatic) compared with MCF-7 cells (poorly invasive/nonmet astatic). In this study, we demonstrate that HP1(Hs alpha), but not HP1(Hs beta) or HP1(Hs gamma), Is down-regulated at the mRNA and protein levels in highly invasive/metastatic breast cancer cell lines. In agreement, little to no nuclear HP1(Hs alpha) staining was observed in these cell lines. In c ontrast, poorly Invasive/nonmetastatic cell lines showed HP1(Hs alpha) loca lization to the nucleus and nuclear membrane, Transfection of MDA-MB-231 ce lls with a green fluorescent protein-HP1(Hs alpha) expression vector decrea sed their ability to invade a collagen IV/laminin/gelatin matrix compared w ith green fluorescent protein-transfected controls. Consistent with the cel l culture studies, immunohistochemical analysis of HP1(Hs alpha) protein lo calization in distant metastatic tissues from breast cancer patients reveal ed a decrease in the staining intensity and percentage of cells expressing HP1(Hs alpha) in seven of nine distant metastatic lesions compared with nor mal mammary and primary tumors. These results demonstrate a role for HP1(Hs alpha) In breast cancer invasion and metastasis. Given the role of HP1 in transcriptional silencing In Drosophila, we propose a model in which HP1(Hs alpha) normally silences genes involved in breast cancer invasion and meta stasis.