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PMID: 19111877 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer.

Cancer cell ·Vol. 15 ·No. 1 ·2009-01-06 ·Pages 9-20

Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, Reiss M, Au JL, Haffty BG, Kang Y

Abstract

Targeted therapy for metastatic diseases relies on the identification of functionally important metastasis genes from a large number of random genetic alterations. Here we use a computational algorithm to map minimal recurrent genomic alterations associated with poor-prognosis breast cancer. 8q22 genomic gain was identified by this approach and validated in an extensive collection of breast tumor samples. Regional gain of 8q22 elevates expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers and is associated with poor clinical outcomes. Functional characterization of MTDH revealed its dual role in promoting metastatic seeding and enhancing chemoresistance. These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk.

MeSH Terms
Aldehyde Dehydrogenase/genetics,metabolism Animals Breast Neoplasms/drug therapy,genetics,metabolism,pathology Cell Adhesion Molecules/genetics,metabolism Cell Line, Tumor Chromosomes, Human, Pair 8/genetics Drug Resistance, Neoplasm Gene Expression Profiling Genome, Human/genetics Humans Membrane Proteins Mice Mice, Nude Neoplasm Metastasis/genetics,pathology Neoplasm Recurrence, Local/genetics,metabolism,pathology Prognosis Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-met RNA-Binding Proteins Receptors, Growth Factor/genetics,metabolism Survival Rate Xenograft Model Antitumor Assays
Chemicals
Cell Adhesion Molecules MTDH protein, human Membrane Proteins Proto-Oncogene Proteins RNA-Binding Proteins Receptors, Growth Factor ALDH3A1 protein, human Aldehyde Dehydrogenase MET protein, human Proto-Oncogene Proteins c-met
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Hu Guohong
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Chong Robert A
Yang Qifeng
Wei Yong
Blanco Mario A
Li Feng
Reiss Michael
Au Jessie L-S
Haffty Bruce G
Kang Yibin
References (40)
40 references, click to expand
  1. Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells.
    Exp Cell Res. 2004 Oct 15;300(1):134-48 PMID: 15383321
  2. Concordance among gene-expression-based predictors for breast cancer.
    N Engl J Med. 2006 Aug 10;355(6):560-9 PMID: 16899776
  3. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis.
    Cancer Cell. 2004 Apr;5(4):365-74 PMID: 15093543
  4. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited.
    Nat Rev Cancer. 2003 Jun;3(6):453-8 PMID: 12778135
  5. Increase of P-glycoprotein-mediated drug resistance by hsp 90 beta.
    Anticancer Drugs. 1996 Nov;7(8):838-45 PMID: 8991187
  6. Primary breast tumor levels of suspected molecular determinants of cellular sensitivity to cyclophosphamide, ifosfamide, and certain other anticancer agents as predictors of paired metastatic tumor levels of these determinants. Rational individualization of cancer chemotherapeutic regimens.
    Cancer Chemother Pharmacol. 2001 Mar;47(3):255-62 PMID: 11320670
  7. Genomic analysis of metastasis reveals an essential role for RhoC.
    Nature. 2000 Aug 3;406(6795):532-5 PMID: 10952316
  8. High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization.
    Breast Cancer Res. 2005;7(6):R1186-98 PMID: 16457699
  9. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer.
    Lancet. 2005 Feb 19-25;365(9460):671-9 PMID: 15721472
  10. Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors.
    Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12963-8 PMID: 12297621
  11. Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion.
    Cancer Res. 2002 Dec 1;62(23):7025-30 PMID: 12460923
  12. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.
    Science. 2007 May 18;316(5827):1039-43 PMID: 17463250
  13. Met, metastasis, motility and more.
    Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25 PMID: 14685170
  14. Tumor necrosis factor-related apoptosis-inducing ligand cooperates with anticancer drugs to overcome chemoresistance in antiapoptotic Bcl-2 family members expressing jurkat cells.
    Clin Cancer Res. 2004 Feb 15;10(4):1463-70 PMID: 14977850
  15. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer.
    Genes Chromosomes Cancer. 2006 Nov;45(11):1033-40 PMID: 16897746
  16. High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability.
    J Cell Mol Med. 2009 Aug;13(8B):2236-2252 PMID: 18681906
  17. Long-term tumor-free survival from treatment with the GFP-TRAIL fusion gene expressed from the hTERT promoter in breast cancer cells.
    Oncogene. 2002 Nov 14;21(52):8020-8 PMID: 12439752
  18. Genes that mediate breast cancer metastasis to lung.
    Nature. 2005 Jul 28;436(7050):518-24 PMID: 16049480
  19. A molecular signature of metastasis in primary solid tumors.
    Nat Genet. 2003 Jan;33(1):49-54 PMID: 12469122
  20. Gene expression profiling predicts clinical outcome of breast cancer.
    Nature. 2002 Jan 31;415(6871):530-6 PMID: 11823860
  21. Functional genomic analysis of cancer metastasis: biologic insights and clinical implications.
    Expert Rev Mol Diagn. 2005 May;5(3):385-95 PMID: 15934815
  22. Antiapoptotic effect of haem oxygenase-1 induced by nitric oxide in experimental solid tumour.
    Br J Cancer. 2003 Mar 24;88(6):902-9 PMID: 12644828
  23. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.
    Cell Stem Cell. 2007 Nov;1(5):555-67 PMID: 18371393
  24. GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis.
    Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9023-8 PMID: 16757564
  25. Bcl-2/adenovirus E1B 19 kDa interacting protein-3 knockdown enables growth of breast cancer metastases in the lung, liver, and bone.
    Cancer Res. 2005 Dec 15;65(24):11689-93 PMID: 16357180
  26. Syndecan-2 mediates adhesion and proliferation of colon carcinoma cells.
    J Biol Chem. 2002 Aug 16;277(33):29730-6 PMID: 12055189
  27. Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1.
    Gene. 2005 Jun 20;353(1):8-15 PMID: 15927426
  28. Comparative genomic hybridization of formalin-fixed, paraffin-embedded breast tumors reveals different patterns of chromosomal gains and losses in fibroadenomas and diploid and aneuploid carcinomas.
    Cancer Res. 1995 Nov 15;55(22):5415-23 PMID: 7585611
  29. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis.
    Nature. 2007 Apr 12;446(7137):765-70 PMID: 17429393
  30. The hallmarks of cancer.
    Cell. 2000 Jan 7;100(1):57-70 PMID: 10647931
  31. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis.
    Cell. 2004 Jun 25;117(7):927-39 PMID: 15210113
  32. A multigenic program mediating breast cancer metastasis to bone.
    Cancer Cell. 2003 Jun;3(6):537-49 PMID: 12842083
  33. Tumor metastasis: mechanistic insights and clinical challenges.
    Nat Med. 2006 Aug;12(8):895-904 PMID: 16892035
  34. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.
    Nature. 2005 Jul 7;436(7047):117-22 PMID: 16001072
  35. Translating insights from the cancer genome into clinical practice.
    Nature. 2008 Apr 3;452(7187):553-63 PMID: 18385729
  36. A gene-expression signature as a predictor of survival in breast cancer.
    N Engl J Med. 2002 Dec 19;347(25):1999-2009 PMID: 12490681
  37. Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene.
    Cell. 2006 Jun 30;125(7):1269-81 PMID: 16814714
  38. The role of the hypoxia-inducible BH3-only proteins BNIP3 and BNIP3L in cancer.
    Cancer Metastasis Rev. 2007 Dec;26(3-4):553-66 PMID: 17805942
  39. A progression puzzle.
    Nature. 2002 Aug 22;418(6900):823 PMID: 12192390
  40. Cancer metastasis: building a framework.
    Cell. 2006 Nov 17;127(4):679-95 PMID: 17110329
Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2008.11.013
Published
2009-01-06
Pages
9-20
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2676231
Subset
IM
Grants
NCI NIH HHS · R01 CA134519 · United States
NCI NIH HHS · R01 CA134519-01 · United States
Databases
GEO
GSE9187
Corrections
CommentIn
PMID: 19111873
External Links
PubMed source DOI: 10.1016/j.ccr.2008.11.013 PMC Full Text View journal details
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