Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2 Journal Article

   


Authors: Basso, A. D.; Solit, D. B.; Munster, P. N.; Rosen, N.
Article Title: Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2
Abstract: Ansamycin antibiotics, such as 17-allylaminogeldanamycin (17-AAG), bind to Hsp90 and regulate its function, resulting in the proteasomal degradation of a subset of signaling proteins that require Hsp90 for conformational maturation. HER2 is a very sensitive target of these drugs. Ansamycins cause RB-dependent G1 arrest that is associated with loss of D-cyclins via a PI3 kinase, Akt dependent pathway. Downregulation of D-cyclin was due, in part, to loss of Akt expression in response to drug. Moreover, in HER2 overexpressing breast cancer cells, 17-AAG caused rapid inhibition of Akt activity prior to any change in Akt protein. Ansamycins caused rapid degradation of HER2 and a concomitant loss in HER3 associated PI3 kinase activity. This led to a loss of Akt activity, dephosphorylation of Akt substrates, and loss of D-cyclin expression. Introduction into cells of a constitutively membrane bound form of PI3 kinase prevented the effects of the drug on Akt activity and D-cyclins. Thus, in breast cancer cells with high HER2, Akt activation by HER2/HER3 heterodimers is required for D-cyclin expression. In murine xenograft models, non-toxic doses of 17-AAG markedly reduced the expression of HER2 and phosphorylation of Akt and inhibited tumor growth. Thus, pharmacological inhibition of Akt activation is achievable with ansamycins and may be useful for the treatment of HER2 driven tumors.
Keywords: protein kinase b; controlled study; protein expression; unclassified drug; human cell; proto-oncogene proteins; nonhuman; mouse; animals; mice; cell division; gene overexpression; breast cancer; animal experiment; animal model; antineoplastic activity; enzyme activation; dose-response relationship, drug; tumor cells, cultured; breast neoplasms; phosphorylation; phosphatidylinositol 3 kinase; mice, inbred balb c; animalia; mus musculus; cancer inhibition; blotting, western; gene expression regulation, neoplastic; nude mouse; protein-serine-threonine kinases; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; murinae; transplantation, heterologous; heat shock protein 90; dimerization; receptor, erbb-2; neoplasm transplantation; akt; antibiotics, antineoplastic; cyclin d1; cyclins; retinoblastoma protein; cell strain mcf 7; g1 phase; benzoquinones; lactams, macrocyclic; 2 morpholino 8 phenylchromone; her2; protein synthesis inhibition; rifabutin; cyclin d; oncogene neu; cyclin d3; ansamycins; ansamycin derivative; cancer graft; 17 allylamino 17 demethoxygeldanamycin; humans; human; female; priority journal; article; 17 allylaminogeldanamycin; mink cell focus-forming virus
Journal Title: Oncogene
Volume: 21
Issue: 8
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2002-02-14
Start Page: 1159
End Page: 1166
Language: English
DOI: 10.1038/sj/onc/1205184
PUBMED: 11850835
PROVIDER: scopus
PMCID: PMC3221005
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-0037075232&partnerID=40&md5=5348c662f021f09a42c08ea34988d791
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. Andrea D. Basso
    32 Basso
  2. Neal Rosen
    425 Rosen
  3. David Solit
    779 Solit
  4. Pamela Munster
    30 Munster
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