title: ErbB2 enhances mammary tumorigenesis, oncogene-independent recurrence and metastasis in a model of IGF-IR-mediated mammary tumorigenesis.
abstract: BACKGROUND
  The type I insulin-like growth factor receptor (IGF-IR) and ErbB2 (Her-2) are receptor tyrosine kinases implicated in human breast cancer. Both proteins are currently the subject of targeted therapeutics that are used in the treatment of breast cancer or which are in clinical trials. The focus of this study was to utilize our inducible model of IGF-IR overexpression to explore the interaction of these two potent oncogenes.
  
  
  RESULTS
  ErbB2 was overexpressed in our RM11A cell line, a murine tumor cell line that overexpresses human IGF-IR in an inducible manner. ErbB2 conferred an accelerated tumor onset and increased tumor incidence after injection of RM11A cells into the mammary glands of syngeneic wild type mice. This was associated with increased proliferation immediately after tumor cell colonization of the mammary gland; however, this effect was lost after tumor establishment. ErbB2 overexpression also impaired the regression of established RM11A tumors following IGF-IR downregulation and enhanced their metastatic potential.
  
  
  CONCLUSIONS
  This study has revealed that even in the presence of vast IGF-IR overexpression, a modest increase in ErbB2 can augment tumor establishment in vivo, mediate resistance to IGF-IR downregulation and facilitate metastasis. This supports the growing evidence suggesting a possible advantage of using IGF-IR and ErbB2-directed therapies concurrently in the treatment of breast cancer.
authors.affiliation: University of Guelph, Department of Biomedical sciences, 50 Stone Rd, E, N1G2W1, Guelph, ON, Canada.
authors.forename: Craig I
authors.initials: CI
authors.lastname: Campbell
authors.forename: James J
authors.initials: JJ
authors.lastname: Petrik
authors.forename: Roger A
authors.initials: RA
authors.lastname: Moorehead
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1
references.citation: Cancer Res. 2008 Mar 1;68(5):1538-45
references.pmid: 18316619
references.citation: Mol Carcinog. 1996 Mar;15(3):227-38
references.pmid: 8597535
references.citation: Breast Cancer Res Treat. 1998 Feb;47(3):295-302
references.pmid: 9516083
references.citation: Ann Oncol. 2008 Nov;19(11):1860-9
references.pmid: 18641009
references.citation: Cancer Res. 1993 Oct 15;53(20):4960-70
references.pmid: 8104689
references.citation: J Biol Chem. 2002 Aug 9;277(32):28468-73
references.pmid: 12000754
references.citation: Nat Rev Cancer. 2007 May;7(5):389-97
references.pmid: 17446858
references.citation: Oncogene. 2007 Mar 8;26(11):1636-44
references.pmid: 16953219
references.citation: J Natl Cancer Inst. 2001 Dec 19;93(24):1852-7
references.pmid: 11752009
references.citation: Mol Pathol. 2002 Apr;55(2):102-9
references.pmid: 11950959
references.citation: Cancer Res. 2005 Dec 1;65(23):11118-28
references.pmid: 16322262
references.citation: Science. 1987 Jul 10;237(4811):178-82
references.pmid: 2885917
references.citation: Cancer Res. 1993 Aug 15;53(16):3736-40
references.pmid: 8339284
references.citation: Mol Cell Biol. 1994 Jun;14(6):3604-12
references.pmid: 8196606
references.citation: Science. 1987 Jan 9;235(4785):177-82
references.pmid: 3798106
references.citation: Clin Cancer Res. 2002 Feb;8(2):347-53
references.pmid: 11839648
references.citation: Oncogene. 2009 May 28;28(21):2152-62
references.pmid: 19377512
references.citation: Nat Rev Cancer. 2005 May;5(5):341-54
references.pmid: 15864276
references.citation: Oncogene. 2005 Nov 10;24(49):7310-9
references.pmid: 16158061
references.citation: Cancer Res. 1998 Mar 15;58(6):1159-64
references.pmid: 9515800
references.citation: Nat Clin Pract Oncol. 2006 May;3(5):269-80
references.pmid: 16683005
references.citation: J Cell Physiol. 1995 Jul;164(1):214-21
references.pmid: 7790393
references.citation: J Clin Invest. 1989 Nov;84(5):1418-23
references.pmid: 2553774
references.citation: Cancer Res. 1997 Mar 15;57(6):1199-205
references.pmid: 9067293
references.citation: Cancer Res. 1998 Nov 15;58(22):5123-9
references.pmid: 9823322
references.citation: J Natl Cancer Inst. 2007 Apr 18;99(8):628-38
references.pmid: 17440164
references.citation: EMBO J. 1996 May 15;15(10):2452-67
references.pmid: 8665853
references.citation: Cancer Res. 2005 May 1;65(9):3781-7
references.pmid: 15867374
references.citation: Cancer Res. 2008 Dec 15;68(24):10238-46
references.pmid: 19074892
references.citation: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references.pmid: 11252954
references.citation: Biochim Biophys Acta. 1997 Jun 7;1332(3):F105-26
references.pmid: 9196021
references.citation: Med Sci Monit. 2002 Dec;8(12):BR521-6
references.pmid: 12503030
references.citation: Cancer Res. 2003 Apr 1;63(7):1445-8
references.pmid: 12670887
references.citation: Oncogene. 2001 Sep 6;20(39):5459-65
references.pmid: 11571643
references.citation: Cancer Gene Ther. 2000 Mar;7(3):384-95
references.pmid: 10766344
references.citation: Oncogene. 1991 Apr;6(4):639-43
references.pmid: 1674366
references.citation: Mol Cell Biol. 1994 Jul;14(7):4588-95
references.pmid: 8007963
references.citation: J Pathol. 1997 Dec;183(4):412-7
references.pmid: 9496257
references.citation: Mol Cell Biol. 1996 Oct;16(10):5276-87
references.pmid: 8816440
references.citation: J Mammary Gland Biol Neoplasia. 2008 Dec;13(4):471-83
references.pmid: 19023648
references.citation: J Mammary Gland Biol Neoplasia. 2008 Dec;13(4):407-13
references.pmid: 19002570
references.citation: Mol Cell Biol. 1994 Nov;14(11):7068-77
references.pmid: 7935422
references.citation: Mol Cancer Res. 2008 May;6(5):819-28
references.pmid: 18505926
references.citation: Oncogene. 2004 Jul 1;23(30):5161-74
references.pmid: 15122317
references.citation: Clin Cancer Res. 2006 Jan 15;12(2):424-31
references.pmid: 16428482
references.citation: Oncogene. 2001 Jan 4;20(1):34-47
references.pmid: 11244498
references.citation: Mol Cancer Ther. 2008 Jul;7(7):1900-8
references.pmid: 18645000
references.citation: Breast Cancer Res Treat. 2001 Aug;68(3):239-48
references.pmid: 11727960
references.citation: Mol Cell Biol. 1990 Feb;10(2):464-73
references.pmid: 2153917
references.citation: Cancer Res. 2007 Apr 15;67(8):3970-5
references.pmid: 17440113
references.citation: Cancer Res. 2006 Jul 15;66(14):7245-52
references.pmid: 16849573
references.citation: Oncogene. 2009 Aug 27;28(34):3009-21
references.pmid: 19581933
references.citation: Horm Metab Res. 2003 Nov-Dec;35(11-12):771-7
references.pmid: 14710357
references.citation: Cancer Res. 2003 Dec 15;63(24):8912-21
references.pmid: 14695208
references.citation: Oncogene. 1992 Sep;7(9):1859-66
references.pmid: 1354348
references.citation: Am J Surg Pathol. 2009 May;33(5):759-67
references.pmid: 19252432
references.citation: Int J Cancer. 2000 Nov 20;89(6):506-13
references.pmid: 11102895
references.citation: Oncogene. 1993 Nov;8(11):2917-23
references.pmid: 8105438
references.citation: Mol Cancer Ther. 2008 Sep;7(9):2589-98
references.pmid: 18765823