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Article: Selective tyrosine hyperphosphorylation of cytoskeletal and stress proteins in primary human breast cancers: Implications for adjuvant use of kinase-inhibitory drugs

TitleSelective tyrosine hyperphosphorylation of cytoskeletal and stress proteins in primary human breast cancers: Implications for adjuvant use of kinase-inhibitory drugs
Authors
Issue Date2004
PublisherAmerican Association for Cancer Research.
Citation
Clinical Cancer Research, 2004, v. 10 n. 12 I, p. 3980-3987 How to Cite?
AbstractPurpose: Small-molecule growth factor receptor inhibitors block cell growth in vitro and downstream signaling in vivo, but controlled trials in patients with advanced solid tumors have yielded disappointing response rates. To clarify this discrepancy, we compared the patterns of tyrosine phosphoprotein expression in human cancer cells and primary tumors. Experimental Design: Immunoaffinity chromatography, two-dimensional electrophoresis, and antiphosphotyrosine immunoblotting were combined with mass spectrometry to determine the phosphoproteomic signatures of 40 matched normal and malignant tissues from patients with breast or liver cancer. The identities and abundance of the detected tyrosine phosphoproteins were compared with those of ligand-responsive A431 cells. Results: Patterns of tyrosine-phosphorylated proteins are similar among normal tissues of the same origin but vary markedly between different tissues. Primary breast tumors exihibit a strikingly homogeneous tyrosine phosphorylation profile, whereas liver cancers display greater phosphoproteomic diversity. The main breast-tumor-specific tyrosine phosphoproteins are cytoskeletal molecules (actin, tubulin, and vimentin) and molecular chaperones (Hsp70, Hsc71, and Grp75). In contrast, control studies in ligand-stimulated A431 human cancer cells revealed an additional phosphorylated subset of promitogenic phosphoproteins (Grb2, Shc, Jnk2, phospholipase C-γ, and phosphatidylinositol 3′-kinase). Conclusions: Identification of cytoskeletal and stress proteins as the most abundant tyrosine phosphoproteins in breast tumors implicates these molecules, rather than promitogenic effectors, as the prime stoichiometric substrates for kinase-inhibitory anticancer drugs in vivo. Because phosphorylated cytoskeletal proteins and chaperones mediate cell motility and apoptotic resistance, respectively, these data raise the intriguing possibility that small-molecule tyrosine kinase inhibitors may be of greatest value either as adjuvant antimetastatic/-invasive drugs or as chemo-/radiosensitizers.
Persistent Identifierhttp://hdl.handle.net/10722/77704
ISSN
2015 Impact Factor: 8.738
2015 SCImago Journal Rankings: 5.314
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLim, YPen_HK
dc.contributor.authorWong, CYen_HK
dc.contributor.authorOoi, LLen_HK
dc.contributor.authorDruker, BJen_HK
dc.contributor.authorEpstein, RJen_HK
dc.date.accessioned2010-09-06T07:34:49Z-
dc.date.available2010-09-06T07:34:49Z-
dc.date.issued2004en_HK
dc.identifier.citationClinical Cancer Research, 2004, v. 10 n. 12 I, p. 3980-3987en_HK
dc.identifier.issn1078-0432en_HK
dc.identifier.urihttp://hdl.handle.net/10722/77704-
dc.description.abstractPurpose: Small-molecule growth factor receptor inhibitors block cell growth in vitro and downstream signaling in vivo, but controlled trials in patients with advanced solid tumors have yielded disappointing response rates. To clarify this discrepancy, we compared the patterns of tyrosine phosphoprotein expression in human cancer cells and primary tumors. Experimental Design: Immunoaffinity chromatography, two-dimensional electrophoresis, and antiphosphotyrosine immunoblotting were combined with mass spectrometry to determine the phosphoproteomic signatures of 40 matched normal and malignant tissues from patients with breast or liver cancer. The identities and abundance of the detected tyrosine phosphoproteins were compared with those of ligand-responsive A431 cells. Results: Patterns of tyrosine-phosphorylated proteins are similar among normal tissues of the same origin but vary markedly between different tissues. Primary breast tumors exihibit a strikingly homogeneous tyrosine phosphorylation profile, whereas liver cancers display greater phosphoproteomic diversity. The main breast-tumor-specific tyrosine phosphoproteins are cytoskeletal molecules (actin, tubulin, and vimentin) and molecular chaperones (Hsp70, Hsc71, and Grp75). In contrast, control studies in ligand-stimulated A431 human cancer cells revealed an additional phosphorylated subset of promitogenic phosphoproteins (Grb2, Shc, Jnk2, phospholipase C-γ, and phosphatidylinositol 3′-kinase). Conclusions: Identification of cytoskeletal and stress proteins as the most abundant tyrosine phosphoproteins in breast tumors implicates these molecules, rather than promitogenic effectors, as the prime stoichiometric substrates for kinase-inhibitory anticancer drugs in vivo. Because phosphorylated cytoskeletal proteins and chaperones mediate cell motility and apoptotic resistance, respectively, these data raise the intriguing possibility that small-molecule tyrosine kinase inhibitors may be of greatest value either as adjuvant antimetastatic/-invasive drugs or as chemo-/radiosensitizers.en_HK
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research.en_HK
dc.relation.ispartofClinical Cancer Researchen_HK
dc.titleSelective tyrosine hyperphosphorylation of cytoskeletal and stress proteins in primary human breast cancers: Implications for adjuvant use of kinase-inhibitory drugsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1078-0432&volume=10&spage=3980&epage=7&date=2004&atitle=Selective+tyrosine+hyperphosphorylation+of+cytoskeletal+and+stress+proteins+in+primary+human+breast+cancers:+Implications+for+adjuvant+use+of+kinase-inhibitory+drugsen_HK
dc.identifier.emailEpstein, RJ: repstein@hku.hken_HK
dc.identifier.authorityEpstein, RJ=rp00501en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-03-0663en_HK
dc.identifier.pmid15217928-
dc.identifier.scopuseid_2-s2.0-3042626249en_HK
dc.identifier.hkuros94917en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-3042626249&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume10en_HK
dc.identifier.issue12 Ien_HK
dc.identifier.spage3980en_HK
dc.identifier.epage3987en_HK
dc.identifier.isiWOS:000222249100007-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLim, YP=7402565211en_HK
dc.identifier.scopusauthoridWong, CY=7404954628en_HK
dc.identifier.scopusauthoridOoi, LL=16245598100en_HK
dc.identifier.scopusauthoridDruker, BJ=7103025565en_HK
dc.identifier.scopusauthoridEpstein, RJ=34975074500en_HK

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