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Molecular Pharmacology

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Research ArticleArticle

Proteasome-Regulated ERBB2 and Estrogen Receptor Pathways in Breast Cancer

Corina Marx, Christina Yau, Surita Banwait, Yamei Zhou, Gary K. Scott, Byron Hann, John W. Park and Christopher C. Benz
Molecular Pharmacology June 2007, 71 (6) 1525-1534; DOI: https://doi.org/10.1124/mol.107.034090
Corina Marx
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Christina Yau
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Surita Banwait
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Yamei Zhou
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Gary K. Scott
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Byron Hann
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John W. Park
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Christopher C. Benz
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Abstract

A major challenge to broadening oncology applications for inhibitors of the ubiquitin-proteasome system (UPS) is the identification of UPS-dependent cancer pathways predictive of tumors responsive to peptidomimetic inhibitors of its 20S core protease activity. To inform clinical studies evaluating UPS inhibitors as breast cancer therapeutics, seven phenotypically diverse human breast cancer cell line models were characterized for their cellular and molecular responses to the clinically approved 20S inhibitor bortezomib (PS341; Velcade), focusing on those overexpressing estrogen receptor (ER) or ERBB2/HER2, because these oncogenic receptor pathways are constitutively activated in ∼80% of all breast cancers. All models demonstrated dose-dependent bortezomib reduction in intracellular 20S activity correlating with cell growth inhibition, and bortezomib IC50 values (concentrations producing 50% growth inhibition) varied directly with pretreatment 20S activities (r = 0.74; *, p < 0.05), suggesting that basal 20S activity may serve as a clinical predictor of tumor responsiveness to UPS inhibition. Reduction in 20S activity (> 60%) was associated with early (24 h) intracellular relocalization of ER (nucleus to cytoplasm) and ERBB2 (plasma membrane to perinuclear lysosomes), buildup of ubiquitinated and Hsp70-associated receptor, degradation and loss of ER and ERBB2 function, and induction of cellular apoptosis. These models were also used to screen a pharmacologic panel of pathway-targeted anticancer agents [4-hydroxy-3-methoxy-5-(benzothiazolylthiomethyl)benzylidenecyanoacetamide (AG825), 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide (AZD6244/ARRY142886), 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride (LY294002), 17-N-allylamino-17-demethoxy geldanamycin (17AAG), and (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (LAQ824)] for those capable of sensitizing to bortezomib. In keeping with the observation that 20S reduction has little effect on mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling in either ER-positive or ERBB2-positive models, only the MEK-1/2 inhibitor AZD6244 consistently improved the antitumor activity of bortezomib.

Footnotes

  • This research was supported in part by National Institutes of Health-sponsored grants R01-CA36773 and R01-CA701468 (Buck Institute) and P50-CA58207 (UCSF Breast SPORE), research sponsorship from Millennium Pharmaceuticals Inc. to the UCSF Comprehensive Cancer Center, and Hazel P. Munroe memorial funding to the Buck Institute.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.034090.

  • ABBREVIATIONS: ER, estrogen receptor; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; AG825, 4-hydroxy-3-methoxy-5-(benzothiazolylthiomethyl)benzylidenecyanoacetamide; PI3K, phosphatidylinositol 3-kinase; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride; AZD6244, 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; LAQ824, (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide; MOPS, 3-(N-morpholino)propanesulfonic acid; NP-40, Nonidet P-40; DAPI, 4,6-diamidino-2-phenylindole; NFκB, nuclear factor κB; Hsp90, 90-kDa heat shock protein; Hsp70, 70-kDa heat shock protein; 17-AAG, 17-N-allylamino-17-demethoxy geldanamycin; NPI-0052, salinosporamide A; HDAC, histone deacetylase; UPS, ubiquitin-proteasome system.

    • Received January 11, 2007.
    • Accepted March 28, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (6)
Molecular Pharmacology
Vol. 71, Issue 6
1 Jun 2007
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Research ArticleArticle

Proteasome-Regulated ERBB2 and Estrogen Receptor Pathways in Breast Cancer

Corina Marx, Christina Yau, Surita Banwait, Yamei Zhou, Gary K. Scott, Byron Hann, John W. Park and Christopher C. Benz
Molecular Pharmacology June 1, 2007, 71 (6) 1525-1534; DOI: https://doi.org/10.1124/mol.107.034090

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Research ArticleArticle

Proteasome-Regulated ERBB2 and Estrogen Receptor Pathways in Breast Cancer

Corina Marx, Christina Yau, Surita Banwait, Yamei Zhou, Gary K. Scott, Byron Hann, John W. Park and Christopher C. Benz
Molecular Pharmacology June 1, 2007, 71 (6) 1525-1534; DOI: https://doi.org/10.1124/mol.107.034090
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