Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes.
Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia is a major mediator of this effect. The mammalian target of rapamycin (mTOR) is activated by insulin and is a key regulator of mammary tumor progression. Pharmacological mTOR inhibition suppresses tumor growth in numerous mammary tumor models in the non-diabetic setting. However, the role of the mTOR pathway in type 2 diabetes-induced tumor growth remains elusive. Herein, we investigated whether the mTOR pathway is implicated in insulin-induced mammary tumor progression in a transgenic mouse model of type 2 diabetes (MKR mice) and evaluated the impact of mTOR inhibition on the diabetic state. Mammary tumor progression was studied in the double transgenic MMTV-Polyoma Virus middle T antigen (PyVmT)/MKR mice and by orthotopic inoculation of PyVmT- and Neu/ErbB2-driven mammary tumor cells (Met-1 and MCNeuA cells respectively). mTOR inhibition by rapamycin markedly suppressed tumor growth in both wild-type and MKR mice. In diabetic animals, however, the promoting action of insulin on tumor growth was completely blunted by rapamycin, despite a worsening of the carbohydrate and lipid metabolism. Taken together, pharmacological mTOR blockade is sufficient to abrogate mammary tumor progression in the setting of hyperinsulinemia, and thus mTOR inhibitors may be an attractive therapeutic modality for breast cancer patients with type 2 diabetes. Careful monitoring of the metabolic state, however, is important as dose adaptations of glucose- and/or lipid-lowering therapy might be necessary.
Fierz
Yvonne
Y
Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Novosyadlyy
Ruslan
R
Vijayakumar
Archana
A
Yakar
Shoshana
S
LeRoith
Derek
D
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004435:Eating / Q000502:physiology; D005260:Female; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
D000903:Antibiotics, Antineoplastic; D001786:Blood Glucose; D007328:Insulin; D014280:Triglycerides; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Int J Cancer. 2007 Aug 15;121(4):856-62
17397032
J Mammary Gland Biol Neoplasia. 2008 Dec;13(4):371-9
19030972
Genes Dev. 2001 Aug 1;15(15):1926-34
11485987
Am J Clin Nutr. 2007 Sep;86(3):s823-35
18265476
Cancer Res. 2007 Jun 1;67(11):5070-5
17545582
Mol Cancer Ther. 2007 Aug;6(8):2188-97
17699716
J Cell Biol. 2004 Jul 19;166(2):213-23
15249583
Clin Cancer Res. 2004 Feb 1;10(3):1013-23
14871980
Cancer Res. 2006 Feb 1;66(3):1500-8
16452206
Mol Cell. 2006 Apr 21;22(2):159-68
16603397
Science. 1991 Aug 23;253(5022):905-9
1715094
Clin Cancer Res. 2006 Apr 15;12(8):2613-21
16638874
Transplant Proc. 2003 May;35(3 Suppl):143S-150S
12742487
Diabetes. 2010 Mar;59(3):686-93
19959755
J Biol Chem. 1999 Apr 2;274(14):9351-6
10092613
J Am Soc Nephrol. 2008 Jul;19(7):1411-8
18385422
Cancer Res. 2005 Jun 15;65(12):5325-36
15958580
Cancer Cell. 2007 Jul;12(1):9-22
17613433
J Am Soc Nephrol. 2005 Oct;16(10):3128-35
16107580
Expert Opin Drug Saf. 2010 May;9(3):459-70
20113155
Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9250-5
18587048
Transplantation. 2007 Dec 27;84(12):1576-83
18165767
Clin Ther. 2000;22 Suppl B:B93-100
10823377
Nephrol Nurs J. 2000 Dec;27(6):623-5
16649344
Ann Oncol. 2008 Aug;19(8):1387-1392
18385198
Clin Exp Metastasis. 2005;22(1):47-59
16132578
J Antibiot (Tokyo). 1975 Oct;28(10):721-6
1102508
In Vitro Cell Dev Biol Anim. 2002 Jun;38(6):326-33
12513120
Am J Pathol. 2003 Nov;163(5):2113-26
14578209
JAMA. 2008 Dec 17;300(23):2754-64
19088353
Clin J Oncol Nurs. 2008 Aug;12(4):639-46
18676330
Nature. 2000 Dec 21-28;408(6815):994-7
11140689
Mol Endocrinol. 2010 Apr;24(4):766-78
20203102
Cancer Res. 2010 Jan 15;70(2):741-51
20068149
Basic Clin Pharmacol Toxicol. 2009 Sep;105(3):188-98
19496779
Cell. 2007 Jun 29;129(7):1261-74
17604717
J Mammary Gland Biol Neoplasia. 2006 Jan;11(1):53-61
16900391
Mol Cell Biol. 1992 Mar;12(3):954-61
1312220
Diabetes. 2008 Apr;57(4):945-57
18174523
Cell Metab. 2008 Dec;8(6):459-67
19041762
Nature. 2004 Sep 9;431(7005):200-5
15306821
Science. 2005 Feb 18;307(5712):1098-101
15718470
Obes Rev. 2007 Sep;8(5):395-408
17716297
Semin Oncol. 2009 Dec;36 Suppl 3:S1-2
19963095
J Pharmacol Sci. 2009 Apr;109(4):496-503
19372632
Cell. 2006 Feb 10;124(3):471-84
16469695