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.
Kirschmann
D A
DA
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
Lininger
R A
RA
Gardner
L M
LM
Seftor
E A
EA
Odero
V A
VA
Ainsztein
A M
AM
Earnshaw
W C
WC
Wallrath
L L
LL
Hendrix
M J
MJ
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