title: Loss of Akt1 or Akt2 delays mammary tumor onset and suppresses tumor growth rate in MTB-IGFIR transgenic mice.
abstract: BACKGROUND
  Akt is a serine/threonine kinase that mediates signaling downstream of tyrosine kinase receptors like the type I insulin-like growth factor receptor (IGF-IR). In fact, we have previously shown that mammary tumors induced by elevated expression of the IGF-IR are associated with hyperactivation of Akt. However, there are three mammalian isoforms of Akt (Akt1, Akt2 and Akt3) and these isoforms regulate distinct physiologic properties within cells. In this manuscript, the impact of disrupting Akt1 or Akt2 in mammary tumors induced by IGF-IR overexpression were examined to determine whether specific Akt isoforms regulate different aspects of mammary tumorigenesis.
  
  
  METHODS
  Akt1 and Akt2 levels were stably ablated in mammary tumors of MTB-IGFIR transgenic mice by crossing MTB-IGFIR transgenic mice with either Akt1(-/-) or Akt2(-/-) mice. Tumor onset, growth rate, and metastasis were determined.
  
  
  RESULTS
  Ablation of Akt1 or Akt2 significantly delayed tumor onset and tumor growth rate but did not significantly alter lung metastasis. Despite the absence of Akt1 or Akt2, mammary tumors that developed in the MTB-IGFIR mice maintained detectable levels of phosphorylated Akt. Disruption of Akt1 or Akt2 did not affect cell morphology or the expression of luminal or basal cytokeratins in mammary tumors.
  
  
  CONCLUSIONS
  Although loss of Akt1 or Akt2 significantly inhibited mammary tumor onset and growth rates the effects were less dramatic than anticipated. Despite the complete loss of Akt1 or Akt2, the level of total phosphorylated Akt remained largely unaffected in the mammary tumors suggesting that loss of one Akt isoform is compensated by enhanced activation of the remaining Akt isoforms. These findings indicate that therapeutic strategies targeting the activation of individual Akt isoforms will prove less effective than simultaneously inhibiting the activity of all three Akt isoforms for the treatment of breast cancer.
authors.affiliation: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G2W1, Canada.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Watson
authors.forename: Roger A
authors.initials: RA
authors.lastname: Moorehead
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D017526:Receptor, IGF Type 1; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
references.citation: Mod Pathol. 2007 Nov;20(11):1200-7
references.pmid: 17885672
references.citation: Cell Signal. 2011 Jan;23(1):19-26
references.pmid: 20688159
references.citation: Science. 2001 Jun 1;292(5522):1728-31
references.pmid: 11387480
references.citation: J Biol Chem. 1999 Apr 2;274(14):9133-6
references.pmid: 10092583
references.citation: Onkologie. 2003 Jun;26(3):290-4
references.pmid: 12845216
references.citation: Oncogene. 2005 Nov 14;24(50):7455-64
references.pmid: 16288292
references.citation: Nat Rev Cancer. 2002 Jun;2(6):442-54
references.pmid: 12189386
references.citation: Mol Cancer Res. 2011 Dec;9(12):1644-57
references.pmid: 22006115
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2359-64
references.pmid: 19174523
references.citation: Biochem Biophys Res Commun. 1995 Nov 13;216(2):526-34
references.pmid: 7488143
references.citation: Breast Cancer Res Treat. 1998 Feb;47(3):255-67
references.pmid: 9516080
references.citation: Proc Natl Acad Sci U S A. 1991 May 15;88(10):4171-5
references.pmid: 1851997
references.citation: Oncogene. 2007 Mar 8;26(11):1636-44
references.pmid: 16953219
references.citation: Genome Biol. 2007;8(5):R76
references.pmid: 17493263
references.citation: Breast Cancer Res. 2003;5(2):101-6
references.pmid: 12631389
references.citation: Cancer Res. 2003 May 1;63(9):2172-8
references.pmid: 12727836
references.citation: Oncogene. 2009 May 28;28(21):2152-62
references.pmid: 19377512
references.citation: Cancer Res. 2007 Dec 15;67(24):11565-75
references.pmid: 18089785
references.citation: Trends Biochem Sci. 2001 Nov;26(11):657-64
references.pmid: 11701324
references.citation: Breast Cancer Res. 2011 Jun 10;13(3):211
references.pmid: 21672282
references.citation: Int J Biol Markers. 2008 Jan-Mar;23(1):1-9
references.pmid: 18409144
references.citation: Cancer Res. 2004 Jan 1;64(1):286-91
references.pmid: 14729636
references.citation: Cancer Treat Rev. 2012 Oct;38(6):689-97
references.pmid: 22118888
references.citation: Cancer Res. 2005 May 1;65(9):3781-7
references.pmid: 15867374
references.citation: Cancer Lett. 2003 Jun 10;195(2):127-37
references.pmid: 12767520
references.citation: Cancer Sci. 2006 Jul;97(7):597-604
references.pmid: 16827799
references.citation: PLoS One. 2011;6(10):e26514
references.pmid: 22028892
references.citation: Cancer Res. 1988 Nov 15;48(22):6429-33
references.pmid: 2972358
references.citation: Cancer Res. 2007 Mar 1;67(5):1979-87
references.pmid: 17332325
references.citation: Cancer Res. 2009 Jun 15;69(12):5057-64
references.pmid: 19491266
references.citation: J Mammary Gland Biol Neoplasia. 2000 Jan;5(1):95-105
references.pmid: 10791772
references.citation: Cell Cycle. 2011 May 15;10(10):1563-70
references.pmid: 21502814
references.citation: Cancer Res. 2007 Jan 1;67(1):167-77
references.pmid: 17210696
references.citation: Hum Pathol. 2004 Dec;35(12):1537-42
references.pmid: 15619214
references.citation: Oncogene. 2011 Jun 2;30(22):2547-57
references.pmid: 21278786
references.citation: Cell. 2004 Aug 6;118(3):277-9
references.pmid: 15294153
references.citation: Biochem J. 1998 Oct 1;335 ( Pt 1):1-13
references.pmid: 9742206
references.citation: Horm Metab Res. 2003 Nov-Dec;35(11-12):794-801
references.pmid: 14710360
references.citation: Oncol Rep. 2005 Jul;14(1):93-8
references.pmid: 15944774
references.citation: Cell. 2007 Jun 29;129(7):1261-74
references.pmid: 17604717
references.citation: Cell Regul. 1991 Dec;2(12):1001-9
references.pmid: 1801921
references.citation: Cancer Res. 2007 Apr 15;67(8):3970-5
references.pmid: 17440113
references.citation: J Cell Physiol. 2006 May;207(2):420-7
references.pmid: 16419029
references.citation: Oncogene. 2012 Jul 5;31(27):3298-309
references.pmid: 22020329
references.citation: Am J Kidney Dis. 1995 Oct;26(4):678-90
references.pmid: 7573028
references.citation: J Cell Biol. 2005 Dec 19;171(6):1023-34
references.pmid: 16365168
references.citation: J Biol Chem. 2001 Oct 19;276(42):38349-52
references.pmid: 11533044
references.citation: Int J Cancer. 2003 Dec 20;107(6):873-7
references.pmid: 14601044
references.citation: J Clin Invest. 2003 Jul;112(2):197-208
references.pmid: 12843127