Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors.

Abstract

Id proteins bind basic helix-loop-helix transcription factors and function as dominant negative inhibitors of gene expression. Id1 and Id3 are required for the recruitment of bone marrow-derived endothelial cell precursors and tumors transplanted into Id-deficient mice demonstrate impaired angiogenesis. Mouse mammary tumor virus-neu mice were bred with Id1-/-Id3+/- mice to ascertain the role of Id1 and Id3 in mammary tumorigenesis in a more physiologically relevant model. In mammary tumors from these mice, Id1 and Id3 expression was restricted to the vascular endothelium. Id1 and Id3 deficiency did not prevent or delay tumor formation but did alter tumor phenotype. The tumors that developed in the Id-deficient mice were larger and cystic with a viable rim of tumor cells surrounding a nonviable core of cellular debris. The Hsp90 chaperone protein is required for cellular survival under condition of environmental stress and for the stability of the neu oncogene. 17-Allylamino-17-demethoxygeldanamycin, an Hsp90 inhibitor, was used to treat these mice. Whereas 17-allylamino-17-demethoxygeldanamycin only modestly delayed the growth of established mammary tumors in WT mice for Id, tumor suppression was dramatically more effective in an Id1- or Id3-deficient background. These data suggest that tumorigenesis can occur in a background of defective angiogenesis but that tumors developing in such an environment may be especially sensitive to inhibitors of neu and stress-activated survival pathways. Thus angiogenesis inhibitors in combination with inhibitors of Hsp90 function should be evaluated for the treatment of advanced breast cancer.

• Authors: Paola de Candia, David B Solit, Dilip Giri, Edi Brogi, Peter M Siegel, Adam B Olshen, William J Muller, Neal Rosen, Robert Benezra
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 21 Pg. 12337-42 (Oct 14 2003) ISSN: 0027-8424 [Print] United States
• PMID: 14526102 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, Neoplasm
• Benzoquinones
• HIF1A protein, human
• HSP90 Heat-Shock Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• Id tumor-specific protein, mouse
• Lactams, Macrocyclic
• Transcription Factors
• Rifabutin
• tanespimycin

Topics

• Animals
• Antigens, Neoplasm (genetics, physiology)
• Benzoquinones
• Female
• Genes, erbB-2
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lactams, Macrocyclic
• Mammary Neoplasms, Experimental (blood supply, drug therapy, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Pathologic (genetics)
• Phenotype
• Rifabutin (analogs & derivatives, pharmacology)
• Transcription Factors (genetics)
• Up-Regulation