ErbB2 enhances mammary tumorigenesis, oncogene-independent recurrence and metastasis in a model of IGF-IR-mediated mammary tumorigenesis.
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.
Campbell
Craig I
CI
University of Guelph, Department of Biomedical sciences, 50 Stone Rd, E, N1G2W1, Guelph, ON, Canada.
Petrik
James J
JJ
Moorehead
Roger A
RA
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*
D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1
Cancer Res. 2008 Mar 1;68(5):1538-45
18316619
Mol Carcinog. 1996 Mar;15(3):227-38
8597535
Breast Cancer Res Treat. 1998 Feb;47(3):295-302
9516083
Ann Oncol. 2008 Nov;19(11):1860-9
18641009
Cancer Res. 1993 Oct 15;53(20):4960-70
8104689
J Biol Chem. 2002 Aug 9;277(32):28468-73
12000754
Nat Rev Cancer. 2007 May;7(5):389-97
17446858
Oncogene. 2007 Mar 8;26(11):1636-44
16953219
J Natl Cancer Inst. 2001 Dec 19;93(24):1852-7
11752009
Mol Pathol. 2002 Apr;55(2):102-9
11950959
Cancer Res. 2005 Dec 1;65(23):11118-28
16322262
Science. 1987 Jul 10;237(4811):178-82
2885917
Cancer Res. 1993 Aug 15;53(16):3736-40
8339284
Mol Cell Biol. 1994 Jun;14(6):3604-12
8196606
Science. 1987 Jan 9;235(4785):177-82
3798106
Clin Cancer Res. 2002 Feb;8(2):347-53
11839648
Oncogene. 2009 May 28;28(21):2152-62
19377512
Nat Rev Cancer. 2005 May;5(5):341-54
15864276
Oncogene. 2005 Nov 10;24(49):7310-9
16158061
Cancer Res. 1998 Mar 15;58(6):1159-64
9515800
Nat Clin Pract Oncol. 2006 May;3(5):269-80
16683005
J Cell Physiol. 1995 Jul;164(1):214-21
7790393
J Clin Invest. 1989 Nov;84(5):1418-23
2553774
Cancer Res. 1997 Mar 15;57(6):1199-205
9067293
Cancer Res. 1998 Nov 15;58(22):5123-9
9823322
J Natl Cancer Inst. 2007 Apr 18;99(8):628-38
17440164
EMBO J. 1996 May 15;15(10):2452-67
8665853
Cancer Res. 2005 May 1;65(9):3781-7
15867374
Cancer Res. 2008 Dec 15;68(24):10238-46
19074892
Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
11252954
Biochim Biophys Acta. 1997 Jun 7;1332(3):F105-26
9196021
Med Sci Monit. 2002 Dec;8(12):BR521-6
12503030
Cancer Res. 2003 Apr 1;63(7):1445-8
12670887
Oncogene. 2001 Sep 6;20(39):5459-65
11571643
Cancer Gene Ther. 2000 Mar;7(3):384-95
10766344
Oncogene. 1991 Apr;6(4):639-43
1674366
Mol Cell Biol. 1994 Jul;14(7):4588-95
8007963
J Pathol. 1997 Dec;183(4):412-7
9496257
Mol Cell Biol. 1996 Oct;16(10):5276-87
8816440
J Mammary Gland Biol Neoplasia. 2008 Dec;13(4):471-83
19023648
J Mammary Gland Biol Neoplasia. 2008 Dec;13(4):407-13
19002570
Mol Cell Biol. 1994 Nov;14(11):7068-77
7935422
Mol Cancer Res. 2008 May;6(5):819-28
18505926
Oncogene. 2004 Jul 1;23(30):5161-74
15122317
Clin Cancer Res. 2006 Jan 15;12(2):424-31
16428482
Oncogene. 2001 Jan 4;20(1):34-47
11244498
Mol Cancer Ther. 2008 Jul;7(7):1900-8
18645000
Breast Cancer Res Treat. 2001 Aug;68(3):239-48
11727960
Mol Cell Biol. 1990 Feb;10(2):464-73
2153917
Cancer Res. 2007 Apr 15;67(8):3970-5
17440113
Cancer Res. 2006 Jul 15;66(14):7245-52
16849573
Oncogene. 2009 Aug 27;28(34):3009-21
19581933
Horm Metab Res. 2003 Nov-Dec;35(11-12):771-7
14710357
Cancer Res. 2003 Dec 15;63(24):8912-21
14695208
Oncogene. 1992 Sep;7(9):1859-66
1354348
Am J Surg Pathol. 2009 May;33(5):759-67
19252432
Int J Cancer. 2000 Nov 20;89(6):506-13
11102895
Oncogene. 1993 Nov;8(11):2917-23
8105438
Mol Cancer Ther. 2008 Sep;7(9):2589-98
18765823