Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: a play in 3 Akts.
The protein serine/threonine kinase Akt, also known as protein kinase B (PKB), is arguably the most important signalling nexus in the cell. Akt integrates a plethora of extracellular signals to generate diverse outcomes, including proliferation, motility, growth, glucose homeostasis, survival, and cell death. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is the second most frequently mutated pathway in cancer, after p53, and mutations in components of this pathway are found in around 70% of breast cancers. Thus, understanding how Akt relays input signals to downstream effectors is critically important for the design of therapeutic strategies to combat breast cancer. In this review, we will discuss the various signals upstream of Akt that impact on its activity, how Akt integrates these signals and modulates the activity of downstream targets to control mammary gland development, and how mutations in components of the pathway result in breast cancer.
Wickenden
Julie A
JA
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK. jaw64@cam.ac.uk
Watson
Christine J
CJ
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt
Cancer Res. 2008 Apr 1;68(7):2122-31
18381417
Mol Endocrinol. 2001 Jun;15(6):867-81
11376107
Cell. 2004 Apr 16;117(2):225-37
15084260
Breast Cancer Res. 2008;10(4):R70
18700973
Nat Cell Biol. 2008 Feb;10(2):127-37
18204440
Science. 2002 May 31;296(5573):1655-7
12040186
Oncogene. 2002 Jan 10;21(2):198-206
11803463
Cell Res. 2008 Aug;18(8):807-16
18626510
Endocrinology. 2002 May;143(5):1872-9
11956170
Mol Cell. 2005 Nov 23;20(4):539-50
16307918
Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):429-34
9892650
Cell Cycle. 2009 Sep 1;8(17):2728-32
19652529
J Biol Chem. 2009 Jul 10;284(28):19018-26
19435886
Clin Cancer Res. 2004 Dec 1;10(23):8059-67
15585641
Cell Cycle. 2005 Jul;4(7):897-900
15970662
Nat Cell Biol. 2005 Apr;7(4):392-8
15793565
Gene. 2006 Jun 7;374:1-9
16675164
J Clin Invest. 2002 Sep;110(6):815-25
12235113
J Mammary Gland Biol Neoplasia. 2000 Jan;5(1):31-42
10791766
Mol Cell Biol. 2001 Mar;21(6):2203-12
11238953
Cancer Res. 2008 Dec 1;68(23):9643-53
19047141
Trends Biochem Sci. 2005 Apr;30(4):194-204
15817396
Nature. 2009 Oct 22;461(7267):1084-91
19847259
Cancer Res. 2009 Jun 15;69(12):5057-64
19491266
J Lipid Res. 2003 Jun;44(6):1100-12
12700340
Development. 2002 Sep;129(17):4159-70
12163417
Science. 1997 May 30;276(5317):1418-20
9162009
Nature. 1999 Sep 2;401(6748):86-90
10485711
Gene Ther. 2003 Nov;10(23):1961-9
14528320
Genes Dev. 2003 Jun 1;17(11):1352-65
12782654
Cancer Res. 2004 May 1;64(9):3171-8
15126356
Mol Biol Cell. 2001 May;12(5):1445-55
11359934
Cancer Res. 2009 Aug 1;69(15):6299-306
19602588
Breast Cancer Res Treat. 2008 Nov;112(2):217-27
18074223
Cancer Res. 2002 Jun 15;62(12):3538-43
12068001
Endocrinology. 2009 Aug;150(8):3611-9
19406949
BMC Mol Biol. 2001;2:2
11178110
Cancer Res. 2009 May 15;69(10):4545-52
19417140
J Cell Biol. 2005 Dec 19;171(6):1023-34
16365168
Biol Cell. 2009 Jan;101(1):13-29
19055486
Nature. 2007 Jul 26;448(7152):439-44
17611497
Genes Dev. 2008 Jun 1;22(11):1490-500
18519641
Sci Signal. 2009 Oct 13;2(92):ra62
19825827
Cell. 1995 Aug 25;82(4):621-30
7664341
Nat Rev Genet. 2006 Aug;7(8):606-19
16847462
J Cell Physiol. 2008 Nov;217(2):468-77
18561256
Cell Metab. 2006 Dec;4(6):475-90
17141631