Control of mammary tumor differentiation by SKI-606 (bosutinib).
C-Src is infrequently mutated in human cancers but it mediates oncogenic signals of many activated growth factor receptors and thus remains a key target for cancer therapy. However, the broad function of Src in many cell types and processes requires evaluation of Src-targeted therapeutics within a normal developmental and immune-competent environment. In an effort to understand the appropriate clinical use of Src inhibitors, we tested an Src inhibitor, SKI-606 (bosutinib), in the MMTV-PyVmT transgenic mouse model of breast cancer. Tumor formation in this model is dependent on the presence of Src, but the necessity of Src kinase activity for tumor formation has not been determined. Furthermore, Src inhibitors have not been examined in an autochthonous tumor model that permits assessment of effects on different stages of tumor progression. Here we show that oral administration of SKI-606 inhibited the phosphorylation of Src in mammary tumors and caused a rapid decrease in the Ezh2 Polycomb group histone H3K27 methyltransferase and an increase in epithelial organization. SKI-606 prevented the appearance of palpable tumors in over 50% of the animals and stopped tumor growth in older animals with pre-existing tumors. These antitumor effects were accompanied by decreased cellular proliferation, altered tumor blood vessel organization and dramatically increased differentiation to lactational and epidermal cell fates. SKI-606 controls the development of mammary tumors by inducing differentiation.
Hebbard
L
L
Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Cecena
G
G
Golas
J
J
Sawada
J
J
Ellies
L G
LG
Charbono
A
A
Williams
R
R
Jimenez
R E
RE
Wankell
M
M
Arndt
K T
KT
DeJoy
S Q
SQ
Rollins
R A
RA
Diesl
V
V
Follettie
M
M
Chen
L
L
Rosfjord
E
E
Cardiff
R D
RD
Komatsu
M
M
Boschelli
F
F
Oshima
R G
RG
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D005260:Female; D020869:Gene Expression Profiling; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009570:Nitriles / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*
D000814:Aniline Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib
J Cell Biol. 2004 Oct 25;167(2):223-9
15504909
Oncogene. 2005 Nov 17;24(51):7599-607
16170374
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11606-11
14500907
Cell. 2006 Apr 21;125(2):301-13
16630818
Genes Dev. 1994 Jan;8(1):23-32
7507074
Mol Cell. 1999 Dec;4(6):915-24
10635317
Oncogene. 2008 Dec 11;27(58):7274-84
18806826
Cell. 1987 Apr 10;49(1):65-73
3103925
Oncogene. 2007 May 24;26(24):3503-10
17173075
Mol Cell Biol. 1992 Mar;12(3):954-61
1312220
Cancer Cell. 2007 Dec;12(6):542-58
18068631
Leukemia. 2009 Mar;23(3):477-85
19039322
Clin Cancer Res. 2006 Mar 1;12(5):1398-401
16533761
Mol Endocrinol. 2007 Jul;21(7):1499-512
17456797
Cancer Res. 1999 Sep 1;59(17):4242-6
10485465
Physiol Genomics. 2007 Feb 12;28(3):323-36
17105756
Genes Dev. 1997 Nov 1;11(21):2835-44
9353253
Nature. 2006 Jan 19;439(7074):353-7
16273092
Am J Pathol. 2002 Sep;161(3):1087-97
12213737
Blood. 2005 Feb 15;105(4):1508-14
15486073
Nature. 1983 Jun 2-8;303(5916):435-9
6304524
Int J Oncol. 1997 Jul;11(1):69-77
21528182
Am J Pathol. 2009 Sep;175(3):1246-54
19661437
J Med Chem. 2001 Nov 8;44(23):3965-77
11689083
Cell. 2009 Mar 20;136(6):1122-35
19303854
Science. 2005 Jan 7;307(5706):58-62
15637262
Nature. 1995 Jun 15;375(6532):577-81
7540725
Oncogene. 2002 Aug 15;21(36):5548-56
12165853
Cancer Res. 2005 Jun 15;65(12):5325-36
15958580
J Mol Med (Berl). 2005 May;83(5):362-76
15662539
Cancer Res. 2007 Feb 15;67(4):1580-8
17308097
Cancer Res. 2006 Feb 15;66(4):2279-86
16489032
Mol Cell Biol. 1998 Apr;18(4):2344-59
9528804
Oncogene. 2005 Aug 25;24(36):5629-36
16007215
Nat Rev Cancer. 2009 Nov;9(11):773-84
19851313
Cancer Res. 2005 Jun 15;65(12):5358-64
15958584
Cancer Cell. 2004 Sep;6(3):209-14
15380511
Ann Oncol. 2008 Aug;19(8):1379-1386
18487549
Cancer Cell. 2008 Feb;13(2):141-52
18242514
Proc Natl Acad Sci U S A. 1978 Sep;75(9):4102-6
212733
J Biol Chem. 2004 Mar 19;279(12):11281-92
14662758
Am J Pathol. 2003 Nov;163(5):2113-26
14578209
Mol Cell Biol. 2003 Dec;23(23):8614-25
14612405
Mol Cell Biol. 1994 Jan;14(1):735-43
7903421
Cancer Res. 2001 Nov 15;61(22):8298-305
11719463
Cancer Res. 2004 Jan 1;64(1):169-79
14729621
BMC Dev Biol. 2008 Jan 23;8:6
18215306
Mol Cancer Ther. 2008 May;7(5):1185-94
18483306
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7849-53
7544006
Science. 2008 Dec 12;322(5908):1695-9
19008416
Nat Rev Clin Oncol. 2009 Oct;6(10):587-95
19787002