Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis.
Mammary epithelial cells constitutively expressing Id-1 protein are unable to differentiate, acquire the ability to proliferate, and invade the extracellular matrix. In addition, Id-1 is aberrantly over-expressed in aggressive and metastatic breast cancer cells, as well as in human breast tumor biopsies from infiltrating carcinomas, suggesting Id-1 might be an important regulator of breast cancer progression. We show that human metastatic breast cancer cells become significantly less invasive in vitro and less metastatic in vivo when Id-1 is down-regulated by stable transduction with antisense Id-1. Expression of the matrix metalloproteinase MT1-MMP is decreased in proportion to the decrease in Id-1 protein levels, representing a potential mechanism for the reduction of invasiveness. Further, to more accurately recapitulate the biology of and potential therapeutic approaches to tumor metastasis, we targeted Id-1 expression systemically in tumor-bearing mice by using a nonviral approach. We demonstrate significant reduction of both Id-1 and MT1-MMP expressions as well as the metastatic spread of 4T1 breast cancer cells in syngeneic BALB/c mice. In conclusion, our studies have identified Id-1 as a critical regulator of breast cancer progression and suggest the feasibility of developing novel therapeutic approaches to target Id-1 expression to reduce breast cancer metastasis in humans.
Fong
Sylvia
S
California Pacific Medical Center, Cancer Research Institute, San Francisco, CA 94115, USA.
Itahana
Yoko
Y
Sumida
Tomoki
T
Singh
Jarnail
J
Coppe
Jean-Philippe
JP
Liu
Yong
Y
Richards
Peter C
PC
Bennington
James L
JL
Lee
Nancy M
NM
Debs
Robert J
RJ
Desprez
Pierre-Yves
PY
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D051798:Inhibitor of Differentiation Protein 1; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D012097:Repressor Proteins; D012190:Retroviridae / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; C507096:Mmp14 protein, mouse; D016376:Oligonucleotides, Antisense; D012097:Repressor Proteins; D014157:Transcription Factors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14