Down-regulation of HP1Hsalpha expression is associated with the metastatic phenotype in breast cancer.
We previously identified a down-regulation in heterochromatin-associated protein 1 (HP1)Hsalpha 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 HP1Hsalpha, but not HP1Hsbeta or HP1Hsgamma, is down-regulated at the mRNA and protein levels in highly invasive/metastatic breast cancer cell lines. In agreement, little to no nuclear HP1Hsalpha staining was observed in these cell lines. In contrast, poorly invasive/nonmetastatic cell lines showed HP1Hsalpha localization to the nucleus and nuclear membrane. Transfection of MDA-MB-231 cells with a green fluorescent protein-HP1Hsalpha 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 HP1Hsalpha protein localization in distant metastatic tissues from breast cancer patients revealed a decrease in the staining intensity and percentage of cells expressing HP1Hsalpha in seven of nine distant metastatic lesions compared with normal mammary and primary tumors. These results demonstrate a role for HP1Hsalpha in breast cancer invasion and metastasis. Given the role of HP1 in transcriptional silencing in Drosophila, we propose a model in which HP1Hsalpha normally silences genes involved in breast cancer invasion and metastasis.
Department of Anatomy and Cell Biology, College of Medicine, University of Iowa Cancer Center, University of Iowa, Iowa City 52242-1109, USA. dawn-kirschmann@uiowa.edu
D A
DA
Kirschmann
R A
RA
Lininger
L M
LM
Gardner
E A
EA
Seftor
V A
VA
Odero
A M
AM
Ainsztein
W C
WC
Earnshaw
L L
LL
Wallrath
M J
MJ
Hendrix
D001940:Breast / Q000166:cytology / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002467:Cell Nucleus / Q000473:pathology; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins; D006801:Humans; D007774:Lactation; D008164:Luminescent Proteins / Q000032:analysis; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D002868:Chromosomal Proteins, Non-Histone; D008164:Luminescent Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D000090266:Chromobox Protein Homolog 5; D049452:Green Fluorescent Proteins