Elevated PI3K signaling drives multiple breast cancer subtypes

Oncotarget

Volumn 2, Issue 6, 2011, Pages 435-447

  Adams, Jessica R ^a,b   Schachter, Nathan F ^a,b   Liu, Jeff C ^c   Zacksenhaus, Eldad ^b,c   Egan, Sean E ^a,b  

^a HOSPITAL FOR SICK CHILDREN   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c UNIVERSITY HEALTH NETWORK   (Canada)

Author keywords

Akt; Breast cancer; Metastasis; Mouse models; PIK3CA; PTEN

Indexed keywords

ADAPTOR PROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; POLYPHOSPHOINOSITIDE; TRASTUZUMAB; TYROSINE KINASE RECEPTOR;

ARTICLE; BREAST CANCER; CANCER CHEMOTHERAPY; CANCER PROGNOSIS; CANCER SURVIVAL; CARCINOGENICITY; ENZYME ACTIVATION; ENZYME ACTIVE SITE; ESTROGEN RECEPTOR POSITIVE BREAST CANCER; GENE DELETION; GENE EXPRESSION REGULATION; GENETIC CODE; GENETIC TRAIT; HUMAN; LINKAGE ANALYSIS; MOLECULAR INTERACTION; MUTATIONAL ANALYSIS; NONHUMAN; PHOSPHATIDYLINOSITOL 3 KINASE GENE; PROTEIN EXPRESSION; PROTEIN FUNCTION; SENSITIVITY ANALYSIS; SIGNAL TRANSDUCTION; TRIPLE NEGATIVE BREAST CANCER; TUMOR GENE; ANIMAL; BIOLOGICAL MODEL; BREAST TUMOR; CARCINOMA; CLASSIFICATION; FEMALE; METABOLISM; MOUSE; PATHOLOGY; PHYSIOLOGY; REVIEW; TUMOR CELL CULTURE; UPREGULATION;

ANIMALS; BREAST NEOPLASMS; CARCINOMA; FEMALE; HUMANS; MICE; MODELS, BIOLOGICAL; PHOSPHATIDYLINOSITOL 3-KINASES; SIGNAL TRANSDUCTION; TUMOR CELLS, CULTURED; UP-REGULATION;

EID: 80052417289     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.285     Document Type: Article

References (158)

1. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008; 27:5497-5510.
2. Whitman M, Downes CP, Keeler M, Keller T, Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988; 332:644-646.
3. Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA, Backer JM. Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit. Mol Cell Biol. 1998; 18:1379-1387.
4. Sun XJ, Liu F. Phosphorylation of IRS proteins Yin-Yang regulation of insulin signaling. Vitam Horm. 2009; 80:351-387.
5. Yenush L, White MF. The IRS-signalling system during insulin and cytokine action. Bioessays. 1997; 19:491-500.
6. Ueki K, Fruman DA, Brachmann SM, Tseng YH, Cantley LC, Kahn CR. Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol Cell Biol. 2002; 22:965-977.
7. Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A, Downward J. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell. 1997; 89:457-467.
8. Gupta S, Ramjaun AR, Haiko P, Wang Y, Warne PH, Nicke B, Nye E, Stamp G, Alitalo K, Downward J. Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell. 2007; 129:957-968.
9. Woodgett JR. Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol. 2005; 17:150-157.
10. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007; 129:1261-1274.
11. Franke TF. PI3K/Akt: getting it right matters. Oncogene. 2008; 27:6473-6488.
12. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009; 122:3589-3594.
13. Laplante M, Sabatini DM. An emerging role of mTOR in lipid biosynthesis. Curr Biol. 2009; 19:R1046-1052.
14. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007; 25:903-915.
15. Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008; 412:179-190.
16. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 2010; 39:171-183.
17. Yecies JL, Manning BD. Transcriptional Control of Cellular Metabolism by mTOR Signaling. Cancer Res. 2011; 71:2815-2820.
18. Yecies JL, Manning BD. mTOR links oncogenic signaling to tumor cell metabolism. J Mol Med. 2011; 89:221-228.
19. Efeyan A, Sabatini DM. mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol. 2010; 22:169-176.
20. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011; 12:21-35.
21. Saci A, Cantley LC, Carpenter CL. Rac1 Regulates the Activity of mTORC1 and mTORC2 and Controls Cellular Size. Mol Cell. 2011; 42:50-61.
22. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006; 11:859-871.
23. McDonald PC, Oloumi A, Mills J, Dobreva I, Maidan M, Gray V, Wederell ED, Bally MB, Foster LJ, Dedhar S. Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res. 2008; 68:1618-1624.
24. Hannigan GE, McDonald PC, Walsh MP, Dedhar S. Integrin-linked kinase: Not so 'pseudo' after all. Oncogene. 2011.
25. Maydan M, McDonald PC, Sanghera J, Yan J, Rallis C, Pinchin S, Hannigan GE, Foster LJ, Ish-Horowicz D, Walsh MP, Dedhar S. Integrin-linked kinase is a functional Mn2+-dependent protein kinase that regulates glycogen synthase kinase-3beta (GSK-3beta) phosphorylation. PLoS One. 2010; 5:e12356.
26. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci U S A. 1998; 95:11211-11216.
27. Wickstrom SA, Lange A, Hess MW, Polleux J, Spatz JP, Kruger M, Pfaller K, Lambacher A, Bloch W, Mann M, Huber LA, Fassler R. Integrin-linked kinase controls microtubule dynamics required for plasma membrane targeting of caveolae. Dev Cell. 2010; 19:574-588.
28. Hannigan G, Troussard AA, Dedhar S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer. 2005; 5:51-63.
29. Voskas D, Ling LS, Woodgett JR. Does GSK-3 provide a shortcut for PI3K activation of Wnt signalling? F1000 Biol Rep. 2010; 2:82.
30. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, Majumder PK, Baselga J, Rosen N. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011; 19:58-71.
31. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275:1943-1947.
32. Rhei E, Kang L, Bogomolniy F, Federici MG, Borgen PI, Boyd J. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res. 1997; 57:3657-3659.
33. Stambolic V, Suzuki A, De la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998; 95:29-39.
34. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A. 1998; 95:13513-13518.
35. Dey N, Crosswell HE, De P, Parsons R, Peng Q, Su JD, Durden DL. The protein phosphatase activity of PTEN regulates SRC family kinases and controls glioma migration. Cancer Res. 2008; 68:1862-1871.
36. Gao D, Inuzuka H, Tseng A, Chin RY, Toker A, Wei W. Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction. Nat Cell Biol. 2009; 11:397-408.
37. Song MS, Carracedo A, Salmena L, Song SJ, Egia A, Malumbres M, Pandolfi PP. Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphataseindependent manner. Cell. 2011; 144:187-199.
38. Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, Barretina J, Lin WM, Rameh L, Salmena L, Pandolfi PP, Cantley LC. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. 2009; 16:115-125.
39. Kawase T, Ohki R, Shibata T, Tsutsumi S, Kamimura N, Inazawa J, Ohta T, Ichikawa H, Aburatani H, Tashiro F, Taya Y. PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt. Cell. 2009; 136:535-550.
40. Gao T, Furnari F, Newton AC. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell. 2005; 18:13-24.
41. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009; 137:873-886.
42. Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL. Breast Cancer Special Feature: Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A. 2011.
43. Zick Y. Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci STKE. 2005; 2005:pe4.
44. Vogt PK, Bader AG, Kang S. Phosphoinositide 3-kinase: from viral oncoprotein to drug target. Virology. 2006; 344:131-138.
45. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene. 2008; 27:5486-5496.
46. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004; 304:554.
47. Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC, Brugge JS. Breast cancerassociated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005; 65:10992-11000.
48. Zhao L, Vogt PK. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci U S A. 2008; 105:2652-2657.
49. Oda K, Okada J, Timmerman L, Rodriguez-Viciana P, Stokoe D, Shoji K, Taketani Y, Kuramoto H, Knight ZA, Shokat KM, McCormick F. PIK3CA cooperates with other phosphatidylinositol 3'-kinase pathway mutations to effect oncogenic transformation. Cancer Res. 2008; 68:8127-8136.
50. Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A. 2001; 98:11598-11603.
51. Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol. 2001; 3:973-982.
52. Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S, Mak TW. Regulation of PTEN transcription by p53. Mol Cell. 2001; 8:317-325.
53. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007; 318:1108-1113.
54. Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, Peters BA, Velculescu VE, Park BH. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther. 2004; 3:772-775.
55. Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004; 64:7678-7681.
56. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005; 65:2554-2559.
57. Wu G, Xing M, Mambo E, Huang X, Liu J, Guo Z, Chatterjee A, Goldenberg D, Gollin SM, Sukumar S, Trink B, Sidransky D. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res. 2005; 7:R609-616.
58. Kadota M, Sato M, Duncan B, Ooshima A, Yang HH, Diaz-Meyer N, Gere S, Kageyama S, Fukuoka J, Nagata T, Tsukada K, Dunn BK, Wakefield LM, Lee MP. Identification of novel gene amplifications in breast cancer and coexistence of gene amplification with an activating mutation of PIK3CA. Cancer Res. 2009; 69:7357-7365.
59. Dillon RL, White DE, Muller WJ. The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer. Oncogene. 2007; 26:1338-1345.
60. Leary RJ, Lin JC, Cummins J, Boca S, Wood LD, Parsons DW, Jones S, Sjoblom T, Park BH, Parsons R, Willis J, Dawson D, Willson JK, Nikolskaya T, Nikolsky Y, Kopelovich L et al. Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers. Proc Natl Acad Sci U S A. 2008; 105:16224-16229.
61. Lopez-Knowles E, O'Toole SA, McNeil CM, Millar EK, Qiu MR, Crea P, Daly RJ, Musgrove EA, Sutherland RL. PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer. 2010; 126:1121-1131.
62. Capodanno A, Camerini A, Orlandini C, Baldini E, Resta ML, Bevilacqua G, Collecchi P. Dysregulated PI3K/Akt/PTEN pathway is a marker of a short disease-free survival in node-negative breast carcinoma. Hum Pathol. 2009; 40:1408-1417.
63. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A, Symmans WF, Pusztai L, Nolden LK, Horlings H, Berns K, Hung MC et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008; 68:6084-6091.
64. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009; 9:463-475.
65. Elsheikh SE, Green AR, Rakha EA, Samaka RM, Ammar AA, Powe D, Reis-Filho JS, Ellis IO. Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype. Br J Cancer. 2008; 99:327-334.
66. Gastaldi S, Comoglio PM, Trusolino L. The Met oncogene and basal-like breast cancer: another culprit to watch out for? Breast Cancer Res. 2010; 12:208.
67. Ponzo MG, Park M. The met receptor tyrosine kinase and basal breast cancer. Cell Cycle. 2010; 9.
68. Savage K, Lambros MB, Robertson D, Jones RL, Jones C, Mackay A, James M, Hornick JL, Pereira EM, Milanezi F, Fletcher CD, Schmitt FC, Ashworth A, Reis-Filho JS. Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis. Clin Cancer Res. 2007; 13:90-101.
69. Wohrle FU, Daly RJ, Brummer T. Function, regulation and pathological roles of the Gab/DOS docking proteins. Cell Commun Signal. 2009; 7:22.
70. Gu H, Neel BG. The "Gab" in signal transduction. Trends Cell Biol. 2003; 13:122-130.
71. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007; 316:1039-1043.
72. Lu X, Kambe F, Cao X, Yamauchi M, Seo H. Insulinlike growth factor-I activation of Akt survival cascade in neuronal cells requires the presence of its cognate receptor in caveolae. Exp Cell Res. 2008; 314:342-351.
73. Ravid D, Maor S, Werner H, Liscovitch M. Caveolin-1 inhibits cell detachment-induced p53 activation and anoikis by upregulation of insulin-like growth factor-I receptors and signaling. Oncogene. 2005; 24:1338-1347.
74. Salani B, Briatore L, Garibaldi S, Cordera R, Maggi D. Caveolin-1 down-regulation inhibits insulin-like growth factor-I receptor signal transduction in H9C2 rat cardiomyoblasts. Endocrinology. 2008; 149:461-465.
75. Almeida A, Muleris M, Dutrillaux B, Malfoy B. The insulin-like growth factor I receptor gene is the target for the 15q26 amplicon in breast cancer. Genes Chromosomes Cancer. 1994; 11:63-65.
76. Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009; 461:809-813.
77. Chan BT, Lee AV. Insulin receptor substrates (IRSs) and breast tumorigenesis. J Mammary Gland Biol Neoplasia. 2008; 13:415-422.
78. Jaiswal BS, Janakiraman V, Kljavin NM, Chaudhuri S, Stern HM, Wang W, Kan Z, Dbouk HA, Peters BA, Waring P, Dela Vega T, Kenski DM, Bowman KK, Lorenzo M, Li H, Wu J et al. Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell. 2009; 16:463-474.
79. Bentires-Alj M, Gil SG, Chan R, Wang ZC, Wang Y, Imanaka N, Harris LN, Richardson A, Neel BG, Gu H. A role for the scaffolding adapter GAB2 in breast cancer. Nat Med. 2006; 12:114-121.
80. Maurer M, Su T, Saal LH, Koujak S, Hopkins BD, Barkley CR, Wu J, Nandula S, Dutta B, Xie Y, Chin YR, Kim DI, Ferris JS, Gruvberger-Saal SK, Laakso M, Wang X et al. 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res. 2009; 69:6299-6306.
81. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007; 448:439-444.
82. Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell. 2007; 12:104-107.
83. Sun T, Aceto N, Meerbrey KL, Kessler JD, Zhou C, Migliaccio I, Nguyen DX, Pavlova NN, Botero M, Huang J, Bernardi RJ, Schmitt E, Hu G, Li MZ, Dephoure N, Gygi SP et al. Activation of Multiple Proto-oncogenic Tyrosine Kinases in Breast Cancer via Loss of the PTPN12 Phosphatase. Cell. 2011; 144:703-718.
84. Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011; 11:289-301.
85. Garcia JM, Silva JM, Dominguez G, Gonzalez R, Navarro A, Carretero L, Provencio M, Espana P, Bonilla F. Allelic loss of the PTEN region (10q23) in breast carcinomas of poor pathophenotype. Breast Cancer Res Treat. 1999; 57:237-243.
86. Garcia JM, Silva J, Pena C, Garcia V, Rodriguez R, Cruz MA, Cantos B, Provencio M, Espana P, Bonilla F. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer. 2004; 41:117-124.
87. Depowski PL, Rosenthal SI, Ross JS. Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol. 2001; 14:672-676.
88. Perren A, Weng LP, Boag AH, Ziebold U, Thakore K, Dahia PL, Komminoth P, Lees JA, Mulligan LM, Mutter GL, Eng C. Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol. 1999; 155:1253-1260.
89. Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, Ceccarelli C, Santini D, Paterini P, Marcu KB, Chieco P, Bonafe M. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007; 117:3988-4002.
90. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell. 2009; 139:693-706.
91. Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell. 2010; 39:493-506.
92. Hartman ZC, Yang XY, Glass O, Lei G, Osada T, Dave SS, Morse MA, Clay TM, Lyerly HK. HER2 overexpression elicits a pro-inflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis. Cancer Res. 2011.
93. Lu Y, Yu Q, Liu JH, Zhang J, Wang H, Koul D, McMurray JS, Fang X, Yung WK, Siminovitch KA, Mills GB. Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. J Biol Chem. 2003; 278:40057-40066.
94. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004; 6:117-127.
95. Agoulnik IU, Hodgson MC, Bowden WA, Ittmann MM. INPP4B: the New Kid on the PI3K Block. Oncotarget. 2011; 2:321-328.
96. Perou CM, Parker JS, Prat A, Ellis MJ, Bernard PS. Clinical implementation of the intrinsic subtypes of breast cancer. Lancet Oncol. 2010; 11:718-719; author reply 720-711.
97. Gatza ML, Lucas JE, Barry WT, Kim JW, Wang Q, Crawford MD, Datto MB, Kelley M, Mathey-Prevot B, Potti A, Nevins JR. A pathway-based classification of human breast cancer. Proc Natl Acad Sci U S A. 2010; 107:6994-6999.
98. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010; 12:R68.
99. Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, Fridlyand J, Sahin A, Agarwal R, Joy C, Liu W, Stivers D, Baggerly K, Carey M, Lluch A, Monteagudo C et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 2009; 69:4116-4124.
100. Weigelt B, Kreike B, Reis-Filho JS. Metaplastic breast carcinomas are basal-like breast cancers: a genomic profiling analysis. Breast Cancer Res Treat. 2009; 117:273-280.
101. Troxell ML, Levine J, Beadling C, Warrick A, Dunlap J, Presnell A, Patterson J, Shukla A, Olson NR, Heinrich MC, Corless CL. High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast. Mod Pathol. 2010; 23:27-37.
102. Li H, Zhu R, Wang L, Zhu T, Li Q, Chen Q, Wang H, Zhu H. PIK3CA mutations mostly begin to develop in ductal carcinoma of the breast. Exp Mol Pathol. 2010; 88:150-155.
103. Dunlap J, Le C, Shukla A, Patterson J, Presnell A, Heinrich MC, Corless CL, Troxell ML. Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Res Treat. 2010; 120:409-418.
104. Lehmann BD, J.A. B, Chen X, Sanders ME, Bapsi Chakravarthy A, Shyr Y, Pietenpol JA. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. Journal of Clinical Investigation. 2011.
105. Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M, Ferro A, Dalla Palma P, Galligioni E, Marchetti A. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res. 2007; 13:6064-6069.
106. Pang H, Flinn R, Patsialou A, Wyckoff J, Roussos ET, Wu H, Pozzuto M, Goswami S, Condeelis JS, Bresnick AR, Segall JE, Backer JM. Differential enhancement of breast cancer cell motility and metastasis by helical and kinase domain mutations of class IA phosphoinositide 3-kinase. Cancer Res. 2009; 69:8868-8876.
107. Marty B, Maire V, Gravier E, Rigaill G, Vincent-Salomon A, Kappler M, Lebigot I, Djelti F, Tourdes A, Gestraud P, Hupe P, Barillot E, Cruzalegui F, Tucker GC, Stern MH, Thiery JP et al. Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basallike breast cancer cells. Breast Cancer Res. 2008; 10:R101.
108. Saal LH, Gruvberger-Saal SK, Persson C, Lovgren K, Jumppanen M, Staaf J, Jonsson G, Pires MM, Maurer M, Holm K, Koujak S, Subramaniyam S, Vallon-Christersson J, Olsson H, Su T, Memeo L et al. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet. 2008; 40:102-107.
109. Fedele CG, Ooms LM, Ho M, Vieusseux J, O'Toole SA, Millar EK, Lopez-Knowles E, Sriratana A, Gurung R, Baglietto L, Giles GG, Bailey CG, Rasko JE, Shields BJ, Price JT, Majerus PW et al. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc Natl Acad Sci U S A. 2010; 107:22231-22236.
110. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, Van De Vijver MJ, Bernards R. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007; 12:395-402.
111. Gong C, Yao Y, Wang Y, Liu B, Wu W, Chen J, Su F, Yao H, Song E. Upregulation of MIR-21 mediates resistance to trastuzumab therapy for breast cancer. J Biol Chem. 2011.
112. O'Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, Duffy MJ, Crown J, O'Donovan N, Slamon DJ. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther. 2010; 9:1489-1502.
113. Chakrabarty A, Rexer BN, Wang SE, Cook RS, Engelman JA, Arteaga CL. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene. 2010; 29:5193-5203.
114. Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 2007; 8:R76.
115. Jiang Z, Deng T, Jones R, Li H, Herschkowitz JI, Liu JC, Weigman VJ, Tsao MS, Lane TF, Perou CM, Zacksenhaus E. Rb deletion in mouse mammary progenitors induces luminal-B or basal-like/EMT tumor subtypes depending on p53 status. J Clin Invest. 2010; 120:3296-3309.
116. Cardiff RD. The pathology of EMT in mouse mammary tumorigenesis. J Mammary Gland Biol Neoplasia. 2010; 15:225-233.
117. Cardiff RD. Mouse models of human breast cancer. Comp Med. 2003; 53:250-253.
118. Ursini-Siegel J, Schade B, Cardiff RD, Muller WJ. Insights from transgenic mouse models of ERBB2-induced breast cancer. Nat Rev Cancer. 2007; 7:389-397.
119. Adams JR, Xu K, Liu JC, Agamez NM, Loch AJ, Wong RG, Wang W, Wright KL, Lane TF, Zacksenhaus E, Egan SE. Cooperation between Pik3ca and p53 Mutations in Mouse Mammary Tumor Formation. Cancer Res. 2011; 71:2706-2717.
120. Jonkers J, Meuwissen R, Van Der Gulden H, Peterse H, Van Der Valk M, Berns A. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet. 2001; 29:418-425.
121. Meyer DS, Brinkhaus H, Muller U, Muller M, Cardiff RD, Bentires-Alj M. Luminal Expression of PIK3CA Mutant H1047R in the Mammary Gland Induces Heterogeneous Tumors. Cancer Res. 2011.
122. Schwertfeger KL, Richert MM, Anderson SM. Mammary gland involution is delayed by activated Akt in transgenic mice. Mol Endocrinol. 2001; 15:867-881.
123. Hutchinson J, Jin J, Cardiff RD, Woodgett JR, Muller WJ. Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression. Mol Cell Biol. 2001; 21:2203-2212.
124. Stambolic V, Tsao MS, Macpherson D, Suzuki A, Chapman WB, Mak TW. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/-mice. Cancer Res. 2000; 60:3605-3611.
125. Li G, Robinson GW, Lesche R, Martinez-Diaz H, Jiang Z, Rozengurt N, Wagner KU, Wu DC, Lane TF, Liu X, Hennighausen L, Wu H. Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. Development. 2002; 129:4159-4170.
126. Jones RA, Campbell CI, Gunther EJ, Chodosh LA, Petrik JJ, Khokha R, Moorehead RA. Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene. 2007; 26:1636-1644.
127. Jones RA, Petrik JJ, Moorehead RA. Preneoplastic changes persist after IGF-IR downregulation and tumor regression. Oncogene. 2010; 29:4779-4786.
128. Hutchinson JN, Jin J, Cardiff RD, Woodgett JR, Muller WJ. Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res. 2004; 64:3171-3178.
129. Schade B, Rao T, Dourdin N, Lesurf R, Hallett M, Cardiff RD, Muller WJ. PTEN deficiency in a luminal ErbB-2 mouse model results in dramatic acceleration of mammary tumorigenesis and metastasis. J Biol Chem. 2009; 284:19018-19026.
130. Zeller KS, Idevall-Hagren O, Stefansson A, Velling T, Jackson SP, Downward J, Tengholm A, Johansson S. PI3-kinase p110alpha mediates beta1 integrin-induced Akt activation and membrane protrusion during cell attachment and initial spreading. Cell Signal. 2010; 22:1838-1848.
131. Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE, Ayala R, Danino M, Karlan BY, Slamon DJ. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res. 2003; 63:196-206.
132. Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, Natesan S, Brugge JS. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelialmesenchymal transition. J Cell Biol. 2005; 171:1023-1034.
133. Maroulakou IG, Oemler W, Naber SP, Tsichlis PN. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTVpolyoma middle T transgenic mice. Cancer Res. 2007; 67:167-177.
134. Dillon RL, Muller WJ. Distinct biological roles for the akt family in mammary tumor progression. Cancer Res. 2010; 70:4260-4264.
135. Dillon RL, Marcotte R, Hennessy BT, Woodgett JR, Mills GB, Muller WJ. Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression. Cancer Res. 2009; 69:5057-5064.
136. Zhou GL, Tucker DF, Bae SS, Bhatheja K, Birnbaum MJ, Field J. Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. J Biol Chem. 2006; 281:36443-36453.
137. Gonzalez E, McGraw TE. The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle. 2009; 8:2502-2508.
138. Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K, Tsichlis PN. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci Signal. 2009; 2:ra62.
139. Polytarchou C, Iliopoulos D, Hatziapostolou M, Kottakis F, Maroulakou I, Struhl K, Tsichlis PN. Akt2 regulates all Akt isoforms and promotes resistance to hypoxia through induction of miR-21 upon oxygen deprivation. Cancer Res. 2011.
140. Brognard J, Sierecki E, Gao T, Newton AC. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell. 2007; 25:917-931.
141. Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, Hennessy BT, Tseng H, Pochanard P, Kim SY, Dunn IF, Schinzel AC, Sandy P, Hoersch S, Sheng Q, Gupta PB et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009; 16:21-32.
142. Wang Y, Zhou D, Phung S, Masri S, Smith D, Chen S. SGK3 is an estrogen-inducible kinase promoting estrogenmediated survival of breast cancer cells. Mol Endocrinol. 2011; 25:72-82.
143. White DE, Cardiff RD, Dedhar S, Muller WJ. Mammary epithelial-specific expression of the integrin-linked kinase (ILK) results in the induction of mammary gland hyperplasias and tumors in transgenic mice. Oncogene. 2001; 20:7064-7072.
144. Pontier SM, Huck L, White DE, Rayment J, Sanguin-Gendreau V, Hennessy B, Zuo D, St-Arnaud R, Mills GB, Dedhar S, Marshall CJ, Muller WJ. Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer. Oncogene. 2010; 29:3374-3385.
145. Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, Koujak S, Ferrando AA, Malmstrom P, Memeo L, Isola J, Bendahl PO, Rosen N, Hibshoosh H, Ringner M, Borg A et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci U S A. 2007; 104:7564-7569.
146. Visvader JE. Cells of origin in cancer. Nature. 2011; 469:314-322.
147. Poon JS, Eves R, Mak AS. Both lipid- and proteinphosphatase activities of PTEN contribute to the p53-PTEN anti-invasion pathway. Cell Cycle. 2010; 9:4450-4454.
148. Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, Xiong Y, Tseng LM, Li SH, Ding Z, Sahin AA, Esteva FJ, Hortobagyi GN, Yu D. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med. 2011; 17:461-469.
149. Marques M, Kumar A, Poveda AM, Zuluaga S, Hernandez C, Jackson S, Pasero P, Carrera AC. Specific function of phosphoinositide 3-kinase beta in the control of DNA replication. Proc Natl Acad Sci U S A. 2009; 106:7525-7530.
150. Jiang X, Chen S, Asara JM, Balk SP. Phosphoinositide 3-kinase pathway activation in phosphate and tensin homolog (PTEN)-deficient prostate cancer cells is independent of receptor tyrosine kinases and mediated by the p110beta and p110delta catalytic subunits. J Biol Chem. 2010; 285:14980-14989.
151. Carvalho S, Milanezi F, Costa JL, Amendoeira I, Schmitt F. PIKing the right isoform: the emergent role of the p110beta subunit in breast cancer. Virchows Arch. 2010; 456:235-243.
152. Dbouk HA, Backer JM. A beta version of life: p110beta takes center stage. Oncotarget. 2010; 1:729-733.
153. Xie X, Zhang D, Zhao B, Lu MK, You M, Condorelli G, Wang CY, Guan KL. I{kappa}B kinase {varepsilon} and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A. 2011; 108:6474-6479.
154. Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, Sjostrom SK, Garraway LA, Weremowicz S, Richardson AL, Greulich H, Stewart CJ, Mulvey LA, Shen RR, Ambrogio L, Hirozane-Kishikawa T et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell. 2007; 129:1065-1079.
155. Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs. Oncotarget. 2010; 1:530-543.
156. Klinakis A, Szabolcs M, Chen G, Xuan S, Hibshoosh H, Efstratiadis A. Igf1r as a therapeutic target in a mouse model of basal-like breast cancer. Proc Natl Acad Sci U S A. 2009; 106:2359-2364.
157. Kalaany NY, Sabatini DM. Tumours with PI3K activation are resistant to dietary restriction. Nature. 2009; 458:725-731.
158. Sheen JH, Zoncu R, Kim D, Sabatini DM. Defective Regulation of Autophagy upon Leucine Deprivation Reveals a Targetable Liability of Human Melanoma Cells In Vitro and In Vivo. Cancer Cell. 2011; 19:613-628.