Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis.

Abstract

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.

• Authors: Sylvia Fong, Yoko Itahana, Tomoki Sumida, Jarnail Singh, Jean-Philippe Coppe, Yong Liu, Peter C Richards, James L Bennington, Nancy M Lee, Robert J Debs, Pierre-Yves Desprez
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 23 Pg. 13543-8 (Nov 11 2003) ISSN: 0027-8424 [Print] United States
• PMID: 14578451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ID1 protein, human
• Idb1 protein, mouse
• Inhibitor of Differentiation Protein 1
• Mmp14 protein, mouse
• Oligonucleotides, Antisense
• Repressor Proteins
• Transcription Factors
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases
• Matrix Metalloproteinase 14

Topics

• Animals
• Blotting, Northern
• Blotting, Western
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Disease Progression
• Down-Regulation
• Extracellular Matrix (metabolism)
• Genetic Therapy (methods)
• Genetic Vectors
• Humans
• Immunohistochemistry
• Inhibitor of Differentiation Protein 1
• Lung Neoplasms (pathology, secondary)
• Matrix Metalloproteinase 14
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microscopy, Fluorescence
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Transplantation
• Oligonucleotides, Antisense (metabolism)
• Phenotype
• Plasmids (metabolism)
• Repressor Proteins
• Retroviridae (genetics)
• Transcription Factors (genetics)