Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis

Clinical Breast Cancer

Volumn 10, Issue SUPPL. 3, 2010, Pages

  McAuliffe, Priscilla ^a   Meric Bernstam, Funda ^a   Mills, Gordon ^a   Gonzalez Angulo, Ana ^a  

^a UNIVERSITY OF TEXAS   (United States)

Author keywords

HER2; Mammalian target of rapamycin; Phosphatidylinositol 3 kinase; PTEN

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 (1H INDAZOL 4 YL) 6 (4 METHANESULFONYL 1 PIPERAZINYLMETHYL) 4 MORPHOLINOTHIENO[3,2 D]PYRIMIDINE; 4 DIALLYLAMINOMETHYLENE 1,3,4,7,10,11,12,13,14,15,16,17 DODECAHYDRO 6 HYDROXY 1 METHOXYMETHYL 10,13 DIMETHYL 3,7,17 TRIOXO 2 OXACYCLOPENTA[A]PHENANTHREN 11 YL ACETATE; 4 [2 (4 AMINO 1,2,5 OXADIAZOL 3 YL) 1 ETHYL 7 (3 PIPERIDINYLMETHOXY) 1H IMIDAZO[4,5 C]PYRIDIN 4 YL] 2 METHYL 3 BUTYN 2 OL; AZD 8055; BGT 226; BKM 120; BYL 719; CAL 101; CARBOPLATIN; DEFOROLIMUS; EVEROLIMUS; GSK 1059615; INK 128; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MK 2206; OSI 027; PACLITAXEL; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B; RAPAMYCIN; RIDAFOROLIMUS; TEMSIROLIMUS; UNCLASSIFIED DRUG; UNINDEXED DRUG; WYE 125132; XL 147; XL 765; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE;

ANGIOGENESIS; ASTHENIA; AUTOPHAGY; BREAST CANCER; BREAST CARCINOGENESIS; CANCER COMBINATION CHEMOTHERAPY; CANCER HORMONE THERAPY; CELL GROWTH; CELL INVASION; CELL MIGRATION; CELL MOTILITY; CELL PROLIFERATION; CELL SURVIVAL; DIARRHEA; DRUG POTENTIATION; DRUG TARGETING; DRUG TOLERABILITY; GENE MUTATION; HUMAN; HYPERGLYCEMIA; HYPERLIPIDEMIA; MUCOSA INFLAMMATION; NAUSEA; NONHUMAN; PNEUMONIA; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; THROMBOCYTOPENIA;

EID: 78649706942     PISSN: 15268209     EISSN: None     Source Type: Journal    
DOI: 10.3816/CBC.2010.s.013     Document Type: Article

References (83)

1. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008; 68:6084-91
2. O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66:1500-8.
3. Gewinner C, Wang ZC, Richardson A, et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 2009; 16:115-25.
4. Brugge J, Hung MC, Mills GB. A new mutational AKT ivation in the PI3K pathway. Cancer Cell 2007; 12:104-7.
5. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124:471-84.
6. Wang L, Harris TE, Lawrence JC, Jr. Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J Biol Chem 2008; 283:15619-27.
7. Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009; 27:2278-87.
8. De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene 2004; 23:3189-99.
9. Soni A, Akcakanat A, Singh G, et al. eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling. Mol Cancer Ther 2008; 7:1782-8.
10. Culjkovic B, Tan K, Orolicki S, et al. The eIF4E RNA regulon promotes the Akt signaling pathway. J Cell Biol 2008; 181:51-63.
11. Jastrzebski K, Hannan KM, Tchoubrieva EB, et al. Coordinate regulation of ribo-some biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors 2007; 25:209-26.
12. Nakamura JL, Garcia E, Pieper RO. S6K1 plays a key role in glial transformation. Cancer Res 2008; 68:6516-23.
13. Bärlund M, Forozan F, Kononen J, et al. Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis. J Natl Cancer Inst 2000; 92:1252-9.
14. Jacinto E, Facchinetti V, Liu D, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 2006; 127:125-37.
15. Yang Q, Inoki K, Ikenoue T, et al. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 2006; 20:2820-32.
16. Pearce LR, Huang X, Boudeau J, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 2007; 405:513-22.
17. Frias MA, Thoreen CC, Jaffe JD, et al. mSin1 is necessary for Akt/PKB phos-phorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006; 16:1865-70.
18. Martin J, Masri J, Bernath A, et al. Hsp70 associates with Rictor and is required for mTORC2 formation and activity. Biochem Biophys Res Commun 2008; 372:578-83.
19. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14:1296-302.
20. Hresko RC, Mueckler M. mTOR rictor is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 2005; 280:40406-16.
21. McDonald PC, Oloumi A, Mills J, et al. Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res 2008; 68:1618-24.
22. Hernández-Negrete I, Carretero-Ortega J, Rosenfeldt H, et al. P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration. J Biol Chem 2007; 282:23708-15.
23. Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signaling. Nat Cell Biol 2002; 4:648-57.
24. Manning BD, Tee AR, Logsdon MN, et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phos-phoinositide 3-kinase/Akt pathway. Mol Cell 2002; 10:151-62.
25. Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002; 4:658-65.
26. Roux P P, Ballif BA, Anjum R, et al. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA 2004; 101:13489-94.
27. Nobukuni T, Joaquin M, Roccio M, et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci USA 2005; 102:14238-43.
28. Agarwal R, Carey M, Hennessy B, et al. PI3K pathway-directed therapeutic strategies in cancer. Curr Opin Investig Drugs 2010; 11:615-28.
29. Hennessy BT, Smith DL, Ram PT, et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005; 4:988-1004.
30. Karni R, de Stanchina E, Lowe SW, et al. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 2007; 14:185-93.
31. Kumar R, Hung MC. Signaling intricacies take center stage in cancer cells. Cancer Res 2005; 65:2511-5.
32. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007; 129:1261-74.
33. Vasudevan KM, Barbie DA, Davies MA, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009; 16:21-32.
34. Zhou B P, Hu MC, Miller SA, et al. HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway. J Biol Chem 2000; 275:8027-31.
35. Chung J, Bachelder RE, Lipscomb EA, et al. Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells. J Cell Biol 2002; 158:165-74.
36. Cui X, Zhang P, Deng W, et al. Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer. Mol Endocrinol 2003; 17:575-88.
37. Johannessen CM, Reczek EE, James M F, et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci USA 2005; 102:8573-8.
38. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997; 16:64-7.
39. Schrager CA, Schneider D, Gruener AC, et al. Clinical and pathological features of breast disease in Cowden's syndrome: an underrecognized syndrome with an increased risk of breast cancer. Hum Pathol 1998; 29:47-53.
40. Bachman KE, Argani P, Samuels Y, et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 2004; 3:772-5.
41. Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 2005; 102:802-7.
42. Barbareschi M, Buttitta F, Felicioni L, et al. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 2007; 13:6064-9.
43. Yim EK, Peng G, Dai H, et al. Rak functions as a tumor suppressor by regulating PTEN protein stability and function. Cancer Cell 2009; 15:304-14.
44. Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007; 448:439-44.
45. Liu H, Radisky DC, Nelson CM, et al. Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. Proc Natl Acad Sci USA 2006; 103:4134-9.
46. Hutchinson JN, Jin J, Cardiff RD, et al. Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res 2004; 64:3171-8.
47. Maroulakou IG, Oemler W, Naber S P, et al. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res 2007; 67:167-77.
48. Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007; 12:395-402.
49. Blanco-Aparicio C, Canamero M, Cecilia Y, et al. Exploring the gain of function contribution of AKT to mammary tumorigenesis in mouse models. PLoS One 2010; 5:e9305.
50. Li G, Robinson GW, Lesche R, et al. Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. Development 2002; 129:4159-70.
51. Thomas GV, Tran C, Mellinghoff IK, et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 2006; 12:122-7.
52. Phung TL, Ziv K, Dabydeen D, et al. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 2006; 10:159-70.
53. Akcakanat A, Singh G, Hung MC, et al. Rapamycin regulates the phosphorylation of rictor. Biochem Biophys Res Commun 2007; 362:330-3.
54. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22:159-68.
55. Stoeltzing O, Meric-Bernstam F, Ellis LM. Intracellular signaling in tumor and endothelial cells: The expected and, yet again, the unexpected. Cancer Cell 2006; 10:89-91.
56. Chan S, Scheulen ME, Johnston S, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005; 23:5314-22.
57. Chresta CM, Davies BR, Hickson I, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 2010; 70:288-98.
58. Yu K, Shi C, Toral-Barza L, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res 2010; 70:621-31.
59. Mondesire WH, Jian W, Zhang H, et al. Targeting mammalian target of rapamy-cin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res 2004; 10:7031-42.
60. Steelman LS, Navolanic PM, Sokolosky ML, et al. Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors. Oncogene 2008; 27:4086-95.
61. Johnston SR. Enhancing the efficacy of hormonal agents with selected targeted agents. Clin Breast Cancer 2009; 9(suppl 1):S28-36.
62. Perez-Tenorio G, Stal O. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer 2002; 86:540-5.
63. Boulay A, Zumstein-Mecker S, Stephan C, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004; 64:252-61.
64. Beeram M, Ta n QT, Tekmal RR, et al. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol 2007; 18:1323-8.
65. Tabernero J, Rojo F, Calvo E, et al. Dose-and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008; 26:1603-10.
66. Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoad-juvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009; 27:2630-7.
67. Johnston SR. New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res 2010; 16:1979-87.
68. Loi S, Haibe-Kains B, Majjaj S, et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA 2010; 107:10208-13.
69. Miller TW, Perez-Torres M, Narasanna A, et al. Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote anti-estrogen resistance in breast cancer. Cancer Res 2009; 69:4192-201.
70. Shi Y, Yan H, Frost P, et al. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/ phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 2005; 4:1533-40.
71. Wan X, Harkavy B, Shen N, et al. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 2007; 26:1932-40.
72. Dowling RJ, Zakikhani M, Fantus IG, et al. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 2007; 67:10804-12.
73. Nahta R, Yu D, Hung MC, et al. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 2006; 3:269-80.
74. Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004; 6:117-27.
75. Lu CH, Wyszomierski SL, Tseng LM, et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res 2007; 13:5883-8.
76. Liedtke C, Broglio K, Moulder S, et al. Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer. Ann Oncol 2009; 20:1953-8.
77. Hoeflich K P, O'Brien C, Boyd Z, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res 2009; 15:4649-64.
78. Saal LH, Gruvberger-Saal SK, Persson C, et al. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet 2008; 40:102-7.
79. Mirzoeva OK, Das D, Heiser LM, et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 2009; 69:565-72.
80. Hidalgo M, Buckner JC, Erlichman C, et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 2006; 12:5755-63.
81. Yee K W, Zeng Z, Konopleva M, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2006; 12:5165-73.
82. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004; 22:909-18.
83. Akcakanat A, Sahin A, Shaye AN, et al. Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases. Cancer 2008; 112:2352-8.