Cancer and Metastasis Reviews

, Volume 29, Issue 4, pp 751–759 | Cite as

The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer

  • Carlos A. Castaneda
  • Hernán Cortes-Funes
  • Henry L. Gomez
  • Eva M. Ciruelos
NON-THEMATIC REVIEW

Abstract

The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediates the effects of a variety of extracellular signals in a number of cellular processes including cell growth, proliferation, and survival. The alteration of integrants of this pathway through mutation of its coding genes increases the activation status of the signaling and can thus lead to cellular transformation. The frequent dysregulation of the PI3K/Akt pathway in breast cancer (BC) and the mediation of this pathway in different processes characteristically implicated in tumorigenesis have attracted the interest of this pathway in BC; however, a more comprehensive understanding of the signaling intricacies is necessary to develop clinical applications of the modulation of this pathway in this pathology. We review a series of experiments examining the contribution of alteration of integrants of this signaling network to human BC and we make an update of the information about the effect of the modulation of this pathway in this cancer.

Keywords

PIK3CA PTEN p110α Akt mTOR breast cancer 

References

  1. 1.
    Dillon, R. L., White, D. E., & Muller, W. J. (2007). The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer. Oncogene, 26(9), 1338–1345.CrossRefPubMedGoogle Scholar
  2. 2.
    Chalhoub, N., & Baker, S. J. (2009). PTEN and the PI3-kinase pathway in cancer. Annual Review of Patholology, 4, 127–150.CrossRefGoogle Scholar
  3. 3.
    Chitnis, M. M., et al. (2008). The type 1 insulin-like growth factor receptor pathway. Clinical Cancer Research, 14(20), 6364–6370.CrossRefPubMedGoogle Scholar
  4. 4.
    Dayanir, V., et al. (2001). Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation. Journal of Biological Chemistry, 276(21), 17686–17692.CrossRefPubMedGoogle Scholar
  5. 5.
    Dillon, R. L., et al. (2009). Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression. Cancer Research, 69(12), 5057–5064.CrossRefPubMedGoogle Scholar
  6. 6.
    Ma, W., & Quirion, R. (2005). The ERK/MAPK pathway, as a target for the treatment of neuropathic pain. Expert Opinion on Therapeutic Targets, 9(4), 699–713.CrossRefPubMedGoogle Scholar
  7. 7.
    Ito, K., Bernardi, R., & Pandolfi, P. P. (2009). A novel signaling network as a critical rheostat for the biology and maintenance of the normal stem cell and the cancer-initiating cell. Current Opinion in Genetics and Development, 19(1), 51–59.CrossRefPubMedGoogle Scholar
  8. 8.
    Hirsch, E., et al. (2008). Taming the PI3K team to hold inflammation and cancer at bay. Pharmacology and Therapeutics, 118(2), 192–205.CrossRefPubMedGoogle Scholar
  9. 9.
    Thiery, J. P., et al. (2009). Epithelial-mesenchymal transitions in development and disease. Cell, 139(5), 871–890.CrossRefPubMedGoogle Scholar
  10. 10.
    Yilmaz, M., & Christofori, G. (2009). EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Reviews, 28(1–2), 15–33.PubMedGoogle Scholar
  11. 11.
    Xia, C., et al. (2006). Regulation of angiogenesis and tumor growth by p110 alpha and AKT1 via VEGF expression. Journal of Cellular Physiology, 209(1), 56–66.CrossRefPubMedGoogle Scholar
  12. 12.
    Liang, Z., et al. (2007). CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochemical and Biophysical Research Communications, 359(3), 716–722.CrossRefPubMedGoogle Scholar
  13. 13.
    Graupera, M., et al. (2008). Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature, 453(7195), 662–666.CrossRefPubMedGoogle Scholar
  14. 14.
    Chin, Y. R., & Toker, A. (2009). Function of Akt/PKB signaling to cell motility, invasion and the tumor stroma in cancer. Cell Signal, 21(4), 470–476.CrossRefPubMedGoogle Scholar
  15. 15.
    S. Loi, B.H.-K., F. Lallemand, L. Pusztai, A. Bardelli, C. Gillett, P. Ellis, M. J. Piccart-Gebhart, W. A. Phillips, G. A. McArthur, C. Sotiriou (2009) Correlation of PIK3CA mutation-associated gene expression signature (PIK3CA-GS) with deactivation of the PI3K pathway and with prognosis within the luminal-B ER + breast cancers. In ASCO. Journal of Clinical Oncology 27:15s (suppl; abstr 533)Google Scholar
  16. 16.
    Noh, W. C., et al. (2008). Activation of the mTOR signaling pathway in breast cancer and its correlation with the clinicopathologic variables. Breast Cancer Research and Treatment, 110(3), 477–483.CrossRefPubMedGoogle Scholar
  17. 17.
    Lopez-Knowles, E., et al. (2010). PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. International Journal of Cancer, 126(5), 1121–1131.Google Scholar
  18. 18.
    Aleskandarany, M. A., et al. (2010). PIK3CA expression in invasive breast cancer: a biomarker of poor prognosis. Breast Cancer Research and Treatment, 122(1), 45–53.CrossRefPubMedGoogle Scholar
  19. 19.
    Marty, B., et al. (2008). Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells. Breast Cancer Research, 10(6), R101.CrossRefPubMedGoogle Scholar
  20. 20.
    Aleskandarany, M. A., et al. (2009). PIK3CA expression in invasive breast cancer: a biomarker of poor prognosis. Breast Cancer Research and Treatment., 122(1), 45–53.CrossRefPubMedGoogle Scholar
  21. 21.
    Park, S. S., & Kim, S. W. (2007). Activated Akt signaling pathway in invasive ductal carcinoma of the breast: correlation with HER2 overexpression. Oncology Reports, 18(1), 139–143.PubMedGoogle Scholar
  22. 22.
    Wu, Y., et al. (2008). Clinical significance of Akt and HER2/neu overexpression in African-American and Latina women with breast cancer. Breast Cancer Research, 10(1), R3.CrossRefPubMedGoogle Scholar
  23. 23.
    Tokunaga, E., et al. (2006). Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. International Journal of Cancer, 118(2), 284–289.CrossRefGoogle Scholar
  24. 24.
    Mottolese M, N.F., Di Benedetto A, Melucci E, Sperduti I, Perracchio L, Buglioni S, Vici P, Nisticò C, Pinnarò P, Fabi A, Bria E Regina Elena (2009) Identification of an Adverse Biologic Profile in Cyclophosphamide/Metotrexate/5-Fluorouracil Treated Early Stage Breast Cancer Patients by Immunohistochemical Analysis of PI3K/p-Akt Pathway Alterations. In San Antonio Breast Cancer Meeting.Google Scholar
  25. 25.
    Kirkegaard, T., et al. (2005). AKT activation predicts outcome in breast cancer patients treated with tamoxifen. Journal of Pathology, 207(2), 139–146.CrossRefPubMedGoogle Scholar
  26. 26.
    Carpten, J. D., et al. (2007). A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature, 448(7152), 439–444.CrossRefPubMedGoogle Scholar
  27. 27.
    Saal, L. H., et al. (2005). PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Research, 65(7), 2554–2559.CrossRefPubMedGoogle Scholar
  28. 28.
    Kalinsky, K., et al. (2009). PIK3CA mutation associates with improved outcome in breast cancer. Clinical Cancer Research, 15(16), 5049–5059.CrossRefPubMedGoogle Scholar
  29. 29.
    Berns, K., et al. (2007). A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell, 12(4), 395–402.CrossRefPubMedGoogle Scholar
  30. 30.
    Stemke-Hale, K., et al. (2008). An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Research, 68(15), 6084–6091.CrossRefPubMedGoogle Scholar
  31. 31.
    Perez-Tenorio, G., et al. (2007). PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clinical Cancer Research, 13(12), 3577–3584.CrossRefPubMedGoogle Scholar
  32. 32.
    Oda, K., et al. (2005). High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Research, 65(23), 10669–10673.CrossRefPubMedGoogle Scholar
  33. 33.
    Li, H., et al. (2009). PIK3CA mutations mostly begin to develop in ductal carcinoma of the breast. Experimental and Molecular Pathology, 88(1), 150–155.CrossRefPubMedGoogle Scholar
  34. 34.
    Bose, S., et al. (2002). Reduced expression of PTEN correlates with breast cancer progression. Human Pathology, 33(4), 405–409.CrossRefPubMedGoogle Scholar
  35. 35.
    Dunlap, J., et al. (2010). Phosphatidylinositol–3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Research and Treatment, 120(2), 409–418.CrossRefPubMedGoogle Scholar
  36. 36.
    Sakr R, C.S., Wynveen C, Barbashina V, Arroyo C, Morrogh M, Heguy A, Olvera N, Rosen N, Morrow M, King T (2009) Reduced/Absent PTEN Expression Is More Common in HER2 Non-Amplified DCIS. In San Antonio Breast Cancer MeetingGoogle Scholar
  37. 37.
    Dupont J, L.A., Knoop A, Ewertz M, Barrett CJ, Hackl W, Bandaru R, Crowell T, Rheinhardt J, Liu W, Gardner H (2009) PIK3CA Mutations Can Be Acquired during Tumor Progression in Breast Cancer. In San Antonio Breast Cancer MeetingGoogle Scholar
  38. 38.
    Oda, K., et al. (2008). PIK3CA cooperates with other phosphatidylinositol 3’-kinase pathway mutations to effect oncogenic transformation. Cancer Research, 68(19), 8127–8136.CrossRefPubMedGoogle Scholar
  39. 39.
    Renner, O., et al. (2008). Activation of phosphatidylinositol 3-kinase by membrane localization of p110alpha predisposes mammary glands to neoplastic transformation. Cancer Research, 68(23), 9643–9653.CrossRefPubMedGoogle Scholar
  40. 40.
    Lai, Y. L., et al. (2008). PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Annals of Surgical Oncology, 15(4), 1064–1069.CrossRefPubMedGoogle Scholar
  41. 41.
    Lerma, E., et al. (2008). Exon 20 PIK3CA mutations decreases survival in aggressive (HER-2 positive) breast carcinomas. Virchows Archiv, 453(2), 133–139.CrossRefPubMedGoogle Scholar
  42. 42.
    Maruyama, N., et al. (2007). Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clinical Cancer Research, 13(2 Pt 1), 408–414.CrossRefPubMedGoogle Scholar
  43. 43.
    Li, S. Y., et al. (2006). PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Research and Treatment, 96(1), 91–95.CrossRefPubMedGoogle Scholar
  44. 44.
    Bachman, K. E., et al. (2004). The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biology & Therapy, 3(8), 772–775.CrossRefGoogle Scholar
  45. 45.
    Campbell, I. G., et al. (2004). Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Research, 64(21), 7678–7681.CrossRefPubMedGoogle Scholar
  46. 46.
    Levine, D. A., et al. (2005). Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clinical Cancer Research, 11(8), 2875–2878.CrossRefPubMedGoogle Scholar
  47. 47.
    Bozhanov, S.S., et al (2010) Alterations in p53, BRCA1, ATM, PIK3CA, and HER2 genes and their effect in modifying clinicopathological characteristics and overall survival of Bulgarian patients with breast cancer. Journal of Cancer Research and Clinical Oncology, 136(11), 1657–1669.Google Scholar
  48. 48.
    Vitolo, M. I., et al. (2009). Deletion of PTEN promotes tumorigenic signaling, resistance to anoikis, and altered response to chemotherapeutic agents in human mammary epithelial cells. Cancer Research, 69(21), 8275–8283.CrossRefPubMedGoogle Scholar
  49. 49.
    Eng, C. (2003). PTEN: one gene, many syndromes. Human Mutation, 22(3), 183–198.CrossRefPubMedGoogle Scholar
  50. 50.
    Chung, M. J., et al. (2004). Inactivation of the PTEN gene protein product is associated with the invasiveness and metastasis, but not angiogenesis, of breast cancer. Pathology International, 54(1), 10–15.CrossRefPubMedGoogle Scholar
  51. 51.
    Depowski, P. L., Rosenthal, S. I., & Ross, J. S. (2001). Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Modern Pathology, 14(7), 672–676.CrossRefPubMedGoogle Scholar
  52. 52.
    Perren, A., et al. (1999). Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. American Journal of Pathology, 155(4), 1253–1260.PubMedGoogle Scholar
  53. 53.
    Tsutsui, S., et al. (2005). Reduced expression of PTEN protein and its prognostic implications in invasive ductal carcinoma of the breast. Oncology, 68(4–6), 398–404.CrossRefPubMedGoogle Scholar
  54. 54.
    Lee, J. S., et al. (2004). Reduced PTEN expression is associated with poor outcome and angiogenesis in invasive ductal carcinoma of the breast. Applied Immunohistochemistry & Molecular Morphology, 12(3), 205–210.CrossRefGoogle Scholar
  55. 55.
    Shoman, N., et al. (2005). Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen. Modern Pathology, 18(2), 250–259.CrossRefPubMedGoogle Scholar
  56. 56.
    Zhu, L., Loo, W. T., & Louis, W. C. (2007). PTEN and VEGF: possible predictors for sentinel lymph node micro-metastasis in breast cancer. Biomedicine & Pharmacotherapy, 61(9), 558–561.CrossRefGoogle Scholar
  57. 57.
    Panigrahi, A. R., et al. (2004). The role of PTEN and its signalling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcome. Journal of Pathology, 204(1), 93–100.CrossRefPubMedGoogle Scholar
  58. 58.
    Saal, L. H., et al. (2007). Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proceedings of the National Academy of Sciences of the United States of America, 104(18), 7564–7569.CrossRefPubMedGoogle Scholar
  59. 59.
    Capodanno, A., et al. (2009). Dysregulated PI3K/Akt/PTEN pathway is a marker of a short disease-free survival in node-negative breast carcinoma. Human Pathology, 40(10), 1408–1417.CrossRefPubMedGoogle Scholar
  60. 60.
    Brugge, J., Hung, M. C., & Mills, G. B. (2007). A new mutational AKTivation in the PI3K pathway. Cancer Cell, 12(2), 104–107.CrossRefPubMedGoogle Scholar
  61. 61.
    Loi, S., et al (2010) PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 107(22), 10208–10213.CrossRefPubMedGoogle Scholar
  62. 62.
    Knuefermann, C., et al. (2003). HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene, 22(21), 3205–3212.CrossRefPubMedGoogle Scholar
  63. 63.
    Liedtke, C., et al. (2008). PIK3CA-activating mutations and chemotherapy sensitivity in stage II–III breast cancer. Breast Cancer Research, 10(2), R27.CrossRefPubMedGoogle Scholar
  64. 64.
    Yang, S. X., et al. (2010). Akt phosphorylation at Ser473 predicts benefit of paclitaxel chemotherapy in node-positive breast cancer. Journal of Clinical Oncology, 28(18), 2974–2981.CrossRefPubMedGoogle Scholar
  65. 65.
    Yamnik, R. L., & Holz, M. K. (2009). mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor alpha serine 167 phosphorylation. FEBS Letters, 584(1), 124–128.CrossRefGoogle Scholar
  66. 66.
    Perez-Tenorio, G., & Stal, O. (2002). Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. British Journal of Cancer, 86(4), 540–545.CrossRefPubMedGoogle Scholar
  67. 67.
    Tokunaga, E., et al. (2006). The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. European Journal of Cancer, 42(5), 629–635.CrossRefPubMedGoogle Scholar
  68. 68.
    Miller TW, F.E., Gonzalez-Angulo AM, Hennessy BT, Mills GB, McKinley ET, Manning HC, Arteaga CL (2009) Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is dependent upon phosphatidylinositol-3 kinase (PI3K) signaling. In San Antonio Breast Cancer MeetingGoogle Scholar
  69. 69.
    Stal, O., et al. (2003). Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Research, 5(2), R37–R44.CrossRefPubMedGoogle Scholar
  70. 70.
    Miller, T. W., et al. (2010). Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. Journal of Clinical Investigation, 120(7), 2406–2413.CrossRefPubMedGoogle Scholar
  71. 71.
    Eichhorn, P. J., et al. (2008). Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Research, 68(22), 9221–9230.CrossRefPubMedGoogle Scholar
  72. 72.
    She, S. C., Ye, Q., Lobo, J., Haskell, K. M., Leander, K. R., DeFeo-Jones, D., et al. (2009). Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. Cancer Research, 69, 3061.Google Scholar
  73. 73.
    Speicher TJ, H.W., Lipton A. (2009) Synergistic Growth Inhibition with a PI3 Kinase/mTOR Inhibitor Plus Lapatinib. In San Antonio Breast Cancer Meeting.Google Scholar
  74. 74.
    Nagata, Y., et al. (2004). PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell, 6(2), 117–127.CrossRefPubMedGoogle Scholar
  75. 75.
    Yao, E., et al. (2009). Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab. Clinical Cancer Research, 15(12), 4147–4156.CrossRefPubMedGoogle Scholar
  76. 76.
    Wang, S. E., et al. (2008). Transforming growth factor beta engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab. Molecular and Cellular Biology, 28(18), 5605–5620.CrossRefPubMedGoogle Scholar
  77. 77.
    O’Brien, N. A., et al. (2010). Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Molecular Cancer Therapeutics, 9(6), 1489–1502.CrossRefPubMedGoogle Scholar
  78. 78.
    Kataoka, Y., et al. (2009). Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Annals of Oncology, 21(2), 255–262.CrossRefPubMedGoogle Scholar
  79. 79.
    Vorkas PA, A.S., Poumpouridou N, Kroupis C, Mavroudis D, Stathopoulos E, Georgoulias V, Lianidou ES (2009) PI3K Pathway Activity and Response to First-Line Chemotherapy in Combination with Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer. In San Antonio Breast Cancer Meeting.Google Scholar
  80. 80.
    Schnell, C. R., et al. (2008). Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Research, 68(16), 6598–6607.CrossRefPubMedGoogle Scholar
  81. 81.
    Courtney, K. D., Corcoran, R. B., & Engelman, J. A. (2010). The PI3K pathway as drug target in human cancer. Journal of Clinical Oncology, 28(6), 1075–1083.CrossRefPubMedGoogle Scholar
  82. 82.
    O’Reilly, K. E., et al. (2006). mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Research, 66(3), 1500–1508.CrossRefPubMedGoogle Scholar
  83. 83.
    Carracedo, A., et al. (2008). Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. Journal of Clinical Investigation, 118(9), 3065–3074.PubMedGoogle Scholar
  84. 84.
    Engelman, J. A., et al. (2008). Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Medicine, 14(12), 1351–1356.CrossRefPubMedGoogle Scholar
  85. 85.
    Bertrand, F. E., et al. (2006). Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells. Leukemia, 20(7), 1254–1260.CrossRefPubMedGoogle Scholar
  86. 86.
    Sharon Barr, S.R., Elizabeth Buck, David Epstein, Mark Miglarese (2010) Co-targeting mTOR and IGF-1R/IR results in synergistic activity against a broad array of tumor cell lines, independent of KRAS mutation status. In AACR 101st Annual Meeting.Google Scholar
  87. 87.
    Serra, V., et al. (2008). NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Research, 68(19), 8022–8030.CrossRefPubMedGoogle Scholar
  88. 88.
    She, Q. B., et al. (2008). Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS ONE, 3(8), e3065.CrossRefPubMedGoogle Scholar
  89. 89.
    Faber, A. C., et al. (2009). Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proceedings of the National Academy of Sciences of the United States of America, 106(46), 19503–19508.CrossRefPubMedGoogle Scholar
  90. 90.
    Sos, M. L., et al. (2009). Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proceedings of the National Academy of Sciences of the United States of America, 106(43), 18351–18356.CrossRefPubMedGoogle Scholar
  91. 91.
    Hoeflich, K. P., et al. (2009). In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clinical Cancer Research, 15(14), 4649–4664.CrossRefPubMedGoogle Scholar
  92. 92.
    Torbett, N. E., et al. (2008). A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochemical Journal, 415(1), 97–110.CrossRefPubMedGoogle Scholar
  93. 93.
    F. Janku, A.M.T., I. Garrido- Laguna, D. S. Hong, A. Naing, G. S. Falchook, J. J. Wheler, S. Fu, S. A. Piha-Paul, R. Kurzrock (2010) PIK3CA, KRAS, and BRAF mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. In ASCO 2010 Meeting. Chicago: Journal of Clinical Oncology Google Scholar
  94. 94.
    Ma, W. W., et al. (2009). [18F]fluorodeoxyglucose positron emission tomography correlates with Akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy. Journal of Clinical Oncology, 27(16), 2697–2704.CrossRefPubMedGoogle Scholar
  95. 95.
    Sabine, V. S., et al. (2010). Gene expression profiling of response to mTOR inhibitor everolimus in pre-operatively treated post-menopausal women with oestrogen receptor-positive breast cancer. Breast Cancer Research and Treatment, 122(2), 419–428.CrossRefPubMedGoogle Scholar
  96. 96.
    Ozbay, T., et al. (2009). In vitro evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing breast cancer cells. Cancer Chemotherapy and Pharmacology, 65(4), 697–706.CrossRefPubMedGoogle Scholar
  97. 97.
    Howes, A. L., et al. (2007). The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Molecular Cancer Therapeutics, 6(9), 2505–2514.CrossRefPubMedGoogle Scholar
  98. 98.
    Garlich, J. R., et al. (2008). A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Research, 68(1), 206–215.CrossRefPubMedGoogle Scholar
  99. 99.
    H. Burris, J.R., S. Sharma, R. S. Herbst, J. Tabernero, J. R. Infante, A. Silva, D. Demanse, W. Hackl, J. Baselga (2010) First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients (pts) with advanced solid tumors. In ASCO 2010 Meeting. Journal of Clinical Oncology Google Scholar
  100. 100.
    D. Sarker, R.K., K. E. Mazina, J. A. Ware, Y. Yan, M. Dresser, M. K. Derynck and J. De-Bono (2009) A phase I study evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of the oral pan-phosphoinositide-3 kinase (PI3K) inhibitor GDC-0941. In ASCO. Journal of Clinical Oncology Google Scholar
  101. 101.
    J. Baselga, M.J.D.J., J. Rodon, H. A. Burris III, D. C. Birle, S. S. De Buck, D. Demanse, Q. C. Ru, M. Goldbrunner, J. C. Bendell (2010) A first-in-human phase I study of BKM120, an oral pan-class I PI3K inhibitor, in patients (pts) with advanced solid tumors. In ASCO 2010 Meeting. Journal of Clinical Oncology Google Scholar
  102. 102.
    Rexer, B. N., Ghosh, R., & Arteaga, C. L. (2009). Inhibition of PI3K and MEK: it is all about combinations and biomarkers. Clinical Cancer Research, 15(14), 4518–4520.CrossRefPubMedGoogle Scholar
  103. 103.
    Meric-Bernstam, F., & Gonzalez-Angulo, A. M. (2009). Targeting the mTOR signaling network for cancer therapy. Journal of Clinical Oncology, 27(13), 2278–2287.CrossRefPubMedGoogle Scholar
  104. 104.
    Ellard, S. L., et al. (2009). Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. Journal of Clinical Oncology, 27(27), 4536–4541.CrossRefPubMedGoogle Scholar
  105. 105.
    Baselga, J., et al. (2009). Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. Journal of Clinical Oncology, 27(16), 2630–2637.CrossRefPubMedGoogle Scholar
  106. 106.
    Chan, S., et al. (2005). Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. Journal of Clinical Oncology, 23(23), 5314–5322.CrossRefPubMedGoogle Scholar
  107. 107.
    Chow LWC, S.Y., Jassem J, Baselga J, Hayes DF, Wolff AC, Hachemi S, Cincotta M, Yu BW, Kong S, Moore L (2006) Phase 3 study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. In San Antonio Breast Cancer Meeting. Breast Cancer Research and TreatmentGoogle Scholar
  108. 108.
    Chen CS, C.M., Imaoka RT, Svahn T, Guardino AE (2009) A Phase I Pilot Study of the Oral mTOR Inhibitor RAD001 in Combination with Capecitabine for Metastatic Breast Cancer. In San Antonio Breast Cancer Meeting.Google Scholar
  109. 109.
    Cardoso F, D.V., Campone M, Massacesi C, Manlius C, Thevenaz P, Zhang Y, Jerusalem G, Sahmoud T, Andre F, Gianni L (2009) Everolimus (Afinitor®), Trastuzumab (H), and Paclitaxel (P) or Vinorelbine (V) in the Treatment of HER-2+ Metastatic Breast Cancer (MBC) Patients (Pts) Pre-Treated with Lapatinib-Containing Therapy: Pooled Analysis of 2 Phase I Studies. In San Antonio Breast Cancer Meeting.Google Scholar
  110. 110.
    G. H. Jerusalem, V.D., F. Cardoso, J. Bergh, A. Fasolo, A. Rorive, C. Manlius, I. Pylvaenaeinen, T. Sahmoud, L. Gianni (2008) Multicenter phase I clinical trial of daily and weekly RAD001 in combination with vinorelbine and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab. In ASCO Annual Meeting. Journal of Clinical Oncology Google Scholar
  111. 111.
    M. Campone, R.O.R., S. Hurvitz, M. Naughton, C. Manlius, L. Vittori, P. Mukhopadhyay, C. Massacesi, T. Sahmoud, F. André (2009) Everolimus plus weekly paclitaxel and trastuzumab in patients (pts) with HER-2+ metastatic breast cancer (MBC) with prior resistance to trastuzumab: a phase I clinical trial. In San Antonio Breast Cancer Meeting.Google Scholar
  112. 112.
    P. H. Morrow, G.M.W., D. J. Booser, J. A. Moore, P. R. Flores, I. E. Krop, E. P. Winer, G. N. Hortobagyi, D. Yu, F. J. Esteva (2010) Phase I/II trial of everolimus (RAD001) and trastuzumab in patients with trastuzumab-resistant, HER2-overexpressing breast cancer. In ASCO 2010 Meeting. Journal of Clinical Oncology Google Scholar
  113. 113.
    F. Dalenc, M.C., P. Hupperets, R. O’Regan, C. Manlius, L. Vittori, P. Mukhopadhyay, C. Massacesi, T. Sahmoud, F. Andre (2010) Everolimus in combination with weekly paclitaxel and trastuzumab in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) with prior resistance to trastuzumab and taxanes: A multicenter phase II clinical trial. In ASCO 2010 Meeting. Journal of Clinical Oncology Google Scholar
  114. 114.
    D. Yardley, M.S., I. Ray-Coquard, B. Melichar, L. Hart, V. Dieras, M. Barve, A. Melnyk, A. Richard, D. Dorer, C. Turner, P. Dodion (2009) Ridaforolimus (AP23573; MK-8669) in combination with trastuzumab for patients with HER2-positive trastuzumab-refractory metastatic breast cancer: a multicenter phase 2 clinical trial. In San Antonio Breast Cancer Meeting.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Carlos A. Castaneda
    • 1
  • Hernán Cortes-Funes
    • 2
  • Henry L. Gomez
    • 1
  • Eva M. Ciruelos
    • 2
  1. 1.Instituto Nacional Enfermedades NeoplásicasLimaPeru
  2. 2.Hospital Universitario 12 de OctubreMadridSpain

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