Somatic expression of PyMT or activated ErbB2 induces estrogen-independent mammary tumorigenesis.
Estrogen signaling is required for the proliferation of normal breast epithelial cells. However, prophylactic inhibition of estrogen signaling fails to prevent 56% of human breast cancer cases. The underlying mechanism is not well understood. Aberrant activation of growth factor signaling is known to provide alternative proliferation pathways in breast cells that are fully transformed, but it is not known whether activation of growth factor signaling can substitute for estrogen signaling in causing aberrant proliferation in the normal breast epithelium. Here, we report that in a retrovirus-based somatic mouse model (replication-competent ALV-LTR splice acceptor/tumor virus A) that closely mimics the evolution of sporadic human breast cancers, mammary epithelial cells harboring PyMT or activated ErbB2 evolve into tumors independent of estrogen or other ovarian functions in contrast to previous observations of estrogen-dependent cancer formation in germ line mouse models of ErbB2 activation. Importantly, ErbB2 activation in normal mammary cells causes estrogen-independent proliferation in both estrogen receptor (ER)-negative cells as well as in normally quiescent ER-positive cells. Therefore, aberrant activation of growth factor signaling contributes to estrogen-independent proliferation of both preneoplastic and cancerous mammary cells, and prophylactic therapy against both growth factor signaling and estrogen signaling may need to be considered in women with increased risk of breast cancer.
Toneff
Michael J
MJ
Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Du
Zhijun
Z
Dong
Jie
J
Huang
Jian
J
Sinai
Parisa
P
Forman
James
J
Hilsenbeck
Susan
S
Schiff
Rachel
R
Huang
Shixia
S
Li
Yi
Y
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2 / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011120:Polyomavirus / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014162:Transfection
D000957:Antigens, Viral, Tumor; D004967:Estrogens; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse
Cancer. 1980 Dec 15;46(12 Suppl):2851-8
6256054
EMBO J. 1988 Jul;7(7):2043-52
2901345
Breast Cancer Res. 2004;6(6):240-5
15535853
Cancer Res. 1995 Jul 15;55(14):3073-7
7606729
Oncogene. 2000 Dec 7;19(52):5982-7
11146549
Oncogene. 2005 Jun 16;24(26):4220-31
15824740
Br J Cancer. 1978 Dec;38(6):745-8
743491
Cancer Res. 2001 Dec 1;61(23):8390-2
11731414
Cancer Lett. 2003 Apr 10;193(1):49-55
12691823
Cancer Res. 2000 Jan 15;60(2):273-5
10667575
Virology. 1998 Sep 1;248(2):305-11
9721239
Cell Growth Differ. 1994 Dec;5(12):1263-74
7696175
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2196-201
16452162
Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19290-5
17158797
Science. 1987 Jan 9;235(4785):177-82
3798106
EMBO J. 1987 Feb;6(2):363-8
3034586
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17396-401
17090666
Cancer Res. 1997 Nov 15;57(22):4987-91
9371488
Cancer Res. 2002 Nov 15;62(22):6376-80
12438218
Cancer Res. 2008 Feb 1;68(3):826-33
18245484
Virology. 1998 Sep 1;248(2):295-304
9721238
Oncogene. 2003 Sep 11;22(39):7998-8011
12970748
Cancer. 1980 Dec 15;46(12 Suppl):2869-71
6256055
Transgenic Res. 2001 Dec;10(6):545-53
11817542
Cancer Res. 2006 Aug 15;66(16):8266-73
16912207
Mol Endocrinol. 2003 May;17(5):818-30
12554767
Nat Med. 2009 Aug;15(8):907-13
19648928
J Natl Cancer Inst. 2003 Mar 5;95(5):353-61
12618500
J Natl Cancer Inst. 2009 Mar 18;101(6):384-98
19276457
Breast Cancer Res Treat. 1995 May;34(2):97-117
7647336
Cancer Cell. 2010 Jan 19;17(1):65-76
20129248
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3728-33
20133707
Cell Cycle. 2007 Apr 1;6(7):823-6
17377492
Folia Biol (Praha). 2004;50(3-4):107-19
15373344
Cancer Res. 2008 May 15;68(10):3637-44
18463397
Cancer Res. 2003 Mar 1;63(5):1067-72
12615724
J Biol Chem. 2004 Aug 6;279(32):33673-83
15190068
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15853-8
14668450
Oncogene. 2004 Sep 9;23(41):6980-5
15286714
Oncogene. 1997 Sep 25;15(13):1513-25
9380403
Nucleic Acids Res. 1988 Jun 24;16(12):5263-76
2838812
J Natl Cancer Inst. 2003 Jan 15;95(2):142-53
12529347
Oncogene. 1995 Jun 15;10(12):2435-46
7784095
Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5455-60
17369357
Oncogene. 1997 Jul 24;15(4):423-35
9242379
Nat Rev Cancer. 2007 May;7(5):389-97
17446858
Cancer Cell. 2007 Aug;12(2):160-70
17692807
J Natl Cancer Inst. 2004 Jun 16;96(12):926-35
15199112
J Mammary Gland Biol Neoplasia. 2009 Dec;14(4):405-9
19936988
Am J Pathol. 2000 Sep;157(3):1031-7
10980141
Oncogene. 2000 Feb 21;19(8):1020-7
10713685
Eur J Cancer. 2003 May;39(7):891-8
12706357
Mol Endocrinol. 1988 Nov;2(11):1027-32
2464745