The PI3K-AKt-mTOR pathway and new tools to prevent acquired hormone resistance in breast cancer

Current Pharmaceutical Biotechnology

Volumn 16, Issue 9, 2015, Pages 804-815

  Nicolini, Andrea ^a   Ferrari, Paola ^a   Kotlarova, Lucie ^b   Rossi, Giuseppe ^c   Biava, Pier M ^d  

^a UNIVERSITY OF PISA   (Italy)

^b Edukafarm   (Czech Republic)

^c INSTITUTE OF CLINICAL PHYSIOLOGY   (Italy)

^d Scientific Institute of Research and Care Multimedica   (Italy)

Author keywords

Acquired hormone resistance; Autophagy; Breast cancer; MYC pathway; PI3K Akt mTOR pathway; PI3K mTOR inhibitors

Indexed keywords

BAFILOMYCIN A1; BUPARLISIB; DALOTUZUMAB; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; GLUCOSE TRANSPORTER 1; GLYCOGEN SYNTHASE KINASE 3; HORMONE RECEPTOR; HYPOXIA INDUCIBLE FACTOR 1; INSULIN; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MYC PROTEIN; NIMBOLIDE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHOPROTEIN PHOSPHATASE 2A; PROGESTERONE RECEPTOR; PROTEIN KINASE B; RIDAFOROLIMUS; SERUM AND GLUCOCORTICOID REGULATED KINASE 1; SOMATOMEDIN C RECEPTOR; SONOLISIB; TUBERIN; MTOR PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR; TARGET OF RAPAMYCIN KINASE;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; ARTICLE; AUTOPHAGY; BREAST CANCER; BREAST METASTASIS; CANCER GROWTH; CANCER IMMUNOTHERAPY; CANCER PATIENT; CELL PROLIFERATION; GENE EXPRESSION; GLUCOSE METABOLISM; HORMONE DEPENDENCE; HORMONE RESISTANCE; HUMAN; INTRACELLULAR SIGNALING; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROGRESSION FREE SURVIVAL; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; TUMOR ESCAPE; ANIMAL; BREAST NEOPLASMS; DRUG RESISTANCE; METABOLISM;

ANIMALS; BREAST NEOPLASMS; DRUG RESISTANCE, NEOPLASM; HUMANS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84938567470     PISSN: 13892010     EISSN: 18734316     Source Type: Journal    
DOI: 10.2174/138920101609150715141545     Document Type: Article

References (88)

1. [1] Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674.
2. [2] Biava, P.M.; Nicolini, A.; Ferrari, P.: Carpi, A.; Sell, S. A systemic approach to cancer treatment: tumor cell reprogramming focused on endocrine-related cancers. Curr. Med. Chem., 2014, 21(9), 1072-1081.
3. [3] Nicolini, A.; Ferrari, P.; Biava, P.M.; Carpi, A. Changing the endocrine dependence of breast cancer: data and hypotheses. Curr. Med. Chem., 2014, 21(9), 1093-1106.
4. [4] Baselga, J.; Campone, M.; Piccart, M.; Burris, H.A. 3rd; Rugo, H.S.; Sahmoud, T.; Noguchi, S.; Gnant, M.; Pritchard, K.I.; Lebrun, F.; Beck, J.T.; Ito, Y.; Yardley, D.; Deleu, I.; Perez, A.; Bachelot, T.; Vittori, L.; Xu, Z.: Mukhopadhyay, P.; Lebwohl, D.; Hortobagyi, G.N. Everolimus in postmenopausal hormonereceptor- positive advanced breast cancer. N. Engl. J. Med., 2012, 366(6), 520-529.
5. [5] http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
6. [6] Porta, C.; Paglino, C.; Mosca, A. Targeting PI3K/Akt/mTOR Signaling in Cancer. Front. Oncol., 2014, 4, 64.
7. [7] Paplomata, E.; O'Regan, R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther. Adv. Med. Oncol., 2014, 6(4), 154-166.
8. [8] Bachelot, T.; Bourgier C.; Cropet, C.; Ray-Coquard, I.; Ferrero, J.M.; Freyer, G.; Abadie-Lacourtoisie, S.; Eymard, J.C.; Debled, M.; Spaëth, D.; Legouffe, E.; Allouache, D.; El Kouri, C.; Pujade- Lauraine, E. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J. Clin. Oncol., 2012, 30(22), 2718-24.
9. [9] Massarweh, S.; Romond, E.; Black, E.P.; Van Meter, E.; Shelton B.; Kadamyan-Melkumian, V.; Stevens, M.; Elledge, R. A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor (ER)-positive breast cancer after aromatase inhibitor (AI) failure. Breast Cancer Res. Treat., 2014, 143(2), 325-332.
10. [10] Bowles, D.W.; Ma, W.W.; Senzer, N.; Brahmer, J.R.; Adjei, A.A.; Davies, M.; Lazar, A.J.; Vo, A.; Peterson, S.; Walker, L.; Hausman, D.; Rudin, C.M.; Jimeno, A. A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br. J. Cancer, 2013, 109(5), 1085-1092.
11. [11] Hong, D.S.; Bowles, D.W.; Falchook, G.S.; Messersmith, W.A.; George, G.C.; O'Bryant, C.L.; Vo, A.C.; Klucher, K.; Herbst, R.S.; Eckhardt, S.G.; Peterson, S.; Hausman, D.F.; Kurzrock, R.; Jimeno, A. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin. Cancer Res., 2012, 18(15), 4173-82.
12. [12] Mayer, I.A.; Abramson, V.G.; Isakoff, S.J.; Forero, A.; Balko, J.M.; Kuba, M.G.; Sanders, M.E.; Yap, J.T.; Van den Abbeele, A.D.; Li Y.; Cantley, L.C.; Winer, E.; Arteaga, C.L. Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol., 2014, 32(12), 1202-9.
13. [13] Markman, B.; Tabernero, J.; Krop, I.; Shapiro, G.I.; Siu, L.; Mita, M.; Melendez, C.M.; Stutvoet, S.; Birle, D.; Anak, O.; Hackl, W.; Baselga, J. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann. Oncol., 2012, 23(9), 2399-408.
14. [14] Di Cosimo, S.; Sathyanarayanan, S.; Bendell, J.C.; Cervantes, A.; Stein, M.N.; Braña, I.; Roda, D.; Haines, B.B.; Zhang, T.; Winter, C.G.; Jha, S.; Xu, Y.; Frazier, J.; Klinghoffer, R.A.; Leighton- Swayze, A.; Song, Y.; Ebbinghaus, S.; Baselga, J. Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: Preclinical characterization and phase I clinical trial. Clin. Cancer Res., 2015, 21(1), 49-59.
15. [15] Lange, C.A.; Yee, D. Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer. Endocr. Relat. Cancer, 2011, 18(4), C19-24.
16. [16] Bardou, V.J.; Arpino, G.; Elledge R.M.; Osborne, C.K.; Clark, G.M. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J. Clin Oncol., 2003, 21(10), 1973-9.
17. [17] Auricchio, F.; Migliaccio, A. In vitro inactivation of estrogen receptor by nuclei: prevention by phosphatase inhibitors. FEBS Lett., 1980, 117(1), 224-226.
18. [18] Tsai, M.J.; O'Malley, B.W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu. Rev. Biochem., 1994, 63, 451-486.
19. [19] Murphy, L.C.; Seekallu, S.V.; Watson, P.H. Clinical significance of estrogen receptor phosphorylation. Endocr. Relat. Cancer, 2011, 18(1), R1-14.
20. [20] Cui, Y.; Zhang, M.; Pestell, R.; Curran, E.M.; Welshons, W.V.; Fuqua, S.A. Phosphorylation of estrogen receptor alpha blocks its acetylation and regulates estrogen sensitivity. Cancer Res., 2004, 64(24), 9199-9208.
21. [21] Yang, C.S.; Xin, H.W.; Kelley, J.B.; Spencer, A.; Brautigan, D.L.; Paschal, B.M. Ligand binding to the androgen receptor induces conformational changes that regulate phosphatase interactions. Mol. Cell Biol., 2007, 27(9), 3390-3404.
22. [22] Miller, T.W.; Rexer, B.N.; Garrett, J.T.; Arteaga, C.L. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res., 2011, 13(6), 224.
23. [23] Rosich, L.; Xargay-Torrent, S; López-Guerra, M; Campo, E; Colomer, D; Roué, G. Counteracting autophagy overcomes resistance to everolimus in mantle cell lymphoma. Clin. Cancer Res., 2012, 18(19), 5278-5289.
24. [24] Chen, Y.L.; Law, P.Y.; Loh, H.H. Inhibition of PI3K/Akt signaling: an emerging paradigm for targeted cancer therapy. Curr. Med. Chem. Anticancer Agents, 2005, 5(6), 575-589.
25. [25] Fruman, D.A.; Meyers, R.E.; Cantley, L.C. Phosphoinositide kinases. Annu. Rev. Biochem., 1998, 67, 481-507.
26. [26] Maehama, T.; Dixon, J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem., 1998, 273(22), 13375-13378.
27. [27] Lu, Y.; Lin, Y.Z.; LaPushin, R.; Cuevas, B.; Fang, X.; Yu, S.X.; Davies, M.A.; Khan, H.; Furui, T.; Mao, M.; Zinner, R.; Hung, M.C.; Steck, P.; Siminovitch, K.; Mills, G.B. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene, 1999, 18(50), 7034-7045.
28. [28] Samuels, Y.; Velculescu, V.E. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle, 2004, 3(10), 1221-1224.
29. [29] Kumar, C.C.; Madison, V. AKT crystal structure and AKT-specific inhibitors. Oncogene, 2005, 24(50), 7493-7501.
30. [30] Zhao, L.; Vogt, P.K. Class I PI3K in oncogenic cellular transformation. Oncogene, 2008, 27(41), 5486-5496.
31. [31] Pawson, T.; Nash, P. Protein-protein interactions define specificity in signal transduction. Genes Dev., 2000, 14(9), 1027-1047.
32. [32] Testa, J.R.; Bellacosa, A. AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. USA, 2001, 98(20), 10983-10985.
33. [33] Fresno Vara, J.A.; Casado, E.; de Castro, J.; Cejas, P.; Belda- Iniesta, C.; González-Barón, M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev., 2004, 30(2), 193-204.
34. [34] Liang, J.; Slingerland, J.M. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle, 2003, 2(4), 339-345.
35. [35] Hay, N.; Sonenberg, N. Upstream and downstream of mTOR. Genes Dev., 2004, 18(16), 1926-1245.
36. [36] Shaw, R.J.; Bardeesy, N.; Manning, B.D.; Lopez, L.; Kosmatka, M.; DePinho, R.A.; Cantley, L.C. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell, 2004, 6(1), 91-99.
37. [37] Engelman, J.A. Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat. Rev. Cancer, 2009, 9(8), 550-562.
38. [38] O'Reilly, K.E.; Rojo, F.; She, Q.B.; Solit, D.; Mills, G.B.; Smith, D.; Lane, H.; Hofmann, F.; Hicklin, D.J.; Ludwig, D.L.; Baselga, J.; Rosen, N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res., 2006, 66(3), 1500-1508.
39. [39] Haruta, T.; Uno, T; Kawahara, J.; Takano, A.; Egawa, K.; Sharma, P.M.; Olefsky, J.M.; Kobayashi, M. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol. Endocrinol., 2000,14(6), 783-94.
40. [40] Shah, O.J.; Wang, Z.; Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol., 2004, 14(18), 1650-1656.
41. [41] Sommer, E.M.; Dry, H.; Cross, D.; Guichard, S.; Davies, B.R.; Alessi, D.R. Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors. Biochem. J., 2013, 452(3), 499-508.
42. [42] Murray, J.T.; Campbell, D.G.; Morrice, N.; Auld, G.C.; Shpiro, N.; Marquez, R.; Peggie, M.; Bain, J.; Bloomberg, G.B.; Grahammer, F.; Lang, F.; Wulff, P.; Kuhl, D.; Cohen, P. Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3. Biochem. J, 2004, 384(Pt 3), 477-488.
43. [43] Fu, X.; Creighton, C.J.; Biswal, NC.; Kumar, V.; Shea, M.; Herrera, S.; Contreras, A.; Gutierrez, C.; Wang, T.; Nanda, S.; Giuliano, M.; Morrison, G.; Nardone, A.; Karlin, K.L.; Westbrook, T.F.; Heiser, L.M.; Anur, P.; Spellman, P.; Guichard, S.M.; Smith, P.D.; Davies, B.R.; Klinowska, T.; Lee, A.V.; Mills, G.B.; Rimawi, M.F.; Hilsenbeck, S.G.; Gray, J.W.; Joshi, A.; Osborne, C.K.; Schiff, R. Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogenactivated protein kinase kinase. Breast Cancer Res., 2014, 16(5), 430.
44. [44] Elumalai, P.; Arunkumar, R.; Benson, C.S.; Sharmila, G.; Arunakaran, J. Nimbolide inhibits IGF-I-mediated PI3K/Akt and MAPK signalling in human breast cancer cell lines (MCF-7 and MDAMB- 231). Cell Biochem. Funct., 2014, 32(5), 476-484.
45. [45] Lang, F.; Artunc, F.; Vallon, V. The physiological impact of the serum and glucocorticoid-inducible kinase SGK1. Curr. Opin. Nephrol. Hypertens., 2009, 18(5), 439-448.
46. [46] Vora, S.R.; Juric, D.; Kim, N.; Mino-Kenudson, M.; Huynh, T.; Costa, C.; Lockerman, E.L.; Pollack, S.F.; Liu, M.; Li, X.; Lehar, J.; Wiesmann, M.; Wartmann, M.; Chen, Y.; Cao, Z.A.; Pinzon- Ortiz, M.; Kim, S.; Schlegel, R.; Huang, A.; Engelman, J.A. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell, 2014, 26(1), 136-149.
47. [47] Armelin, H.A.; Armelin, M.C.; Kelly, K.; Stewart, T.; Leder, P.; Cochran, B.H.; Stiles, C.D. Functional role for c-myc in mitogenic response to platelet-derived growth factor. Nature, 1984, 310(5979), 655-660.
48. [48] Kelly, K.; Cochran, B.H.; Stiles, C.D.; Leder, P. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and plateletderived growth factor. Cell, 1983, 35(3 Pt 2), 603-610.
49. [49] Chen, Y.; Olopade, O.I. MYC in breast tumor progression. Expert Rev. Anticancer Ther., 2008, 8(10), 1689-1698.
50. [50] Zhu, J.; Blenis, J.; Yuan, J. Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc. Natl. Acad. Sci. USA, 2008, 105(18), 6584-6589.
51. [51] Chen, W.; Possemato, R.; Campbell, K.T.; Plattner, C.A.; Pallas, D.C.; Hahn, W.C. Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell, 2004, 5(2), 127-136.
52. [52] Sablina, A.A.; Chen, W.; Arroyo, J.D.; Corral, L.; Hector, M.; Bulmer, S.E.; DeCaprio, J.A.; Hahn, W.C. The tumor suppressor PP2A Abeta regulates the RalA GTPase. Cell, 2007, 129(5), 969-982.
53. [53] Zhao, J.J.; Gjoerup, O.V.; Subramanian, R.R.; Cheng, Y.; Chen, W.; Roberts, T.M.; Hahn, W.C. Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3- kinase. Cancer Cell, 2003, 3(5), 483-495.
54. [54] Tan J.; Lee P.L.; Li Z.; Jiang X.; Lim Y.C.; Hooi S.C.; Yu Q. B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell, 2010, 18(5), 459-71.
55. [55] Ilic, N; Utermark, T.; Widlund, H.R.; Roberts, T.M. PI3K-targeted therapy can be evaded by gene amplification along the MYCeukaryotic translation initiation factor 4E (eIF4E) axis. Proc. Natl. Acad. Sci. USA, 2011, 108(37), E699-708.
56. [56] Jones, R.M.; Branda, J.; Johnston, K.A.; Polymenis, M.; Gadd, M.; Rustgi, A.; Callanan, L.; Schmidt, E.V. An essential E box in the promoter of the gene encoding the Mrna cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc. Mol. Cell Biol., 1996, 16(9), 4754-4764.
57. [57] Rosenwald, I.B.; Rhoads, D.B.; Callanan, L.D.; Isselbacher, K.J.; Schmidt, E.V. Increased expression of eukaryotic translation initiation factors eIF-4E and eIF-2 alpha in response to growth induction by c-myc. Proc. Natl. Acad. Sci. USA, 1993, 90(13), 6175-6178.
58. [58] Dang, C.V. MYC on the path to cancer. Cell, 2012, 149(1), 22-35.
59. [59] Chen, S.; Rehman, S.K.; Zhang, W.; Wen, A.; Yao, L.; Zhang, J. Autophagy is a therapeutic target in anticancer drug resistance. Biochim. Biophys. Acta, 2010, 1806(2), 220-229.
60. [60] Chen, N.; Karantza-Wadsworth, V. Role and regulation of autophagy in cancer. Biochim. Biophys. Acta, 2009, 1793(9), 1516-1523.
61. [61] Qin, L.; Wang, Z.; Tao, L.; Wang, Y. ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy, 2010, 6(2), 239-247.
62. [62] Maurer, M.; Su, T.; Saal, L.H.; Koujak, S.; Hopkins, B.D.; Barkley, C.R.; Wu, J.; Nandula, S.; Dutta, B.; Xie, Y.; Chin, Y.R.; Kim, D.I.; Ferris, J.S.; Gruvberger-Saal, S.K.; Laakso, M.; Wang, X.; Memeo, L.; Rojtman, A.; Matos, T.; Yu, J.S.; Cordon-Cardo, C.; Isola, J.; Terry, M.B.; Toker, A.; Mills, G.B.; Zhao, J.J.; Murty, V.V.; Hibshoosh, H.; Parsons, R. 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3- kinase pathway in breast carcinoma. Cancer Res., 2009, 69(15), 6299-6306.
63. [63] Peifer, C.; Alessi, D.R. Small-molecule inhibitors of PDK1. Chem. Med. Chem., 2008, 3(12), 1810-1838.
64. [64] Shankaran, V.; Ikeda, H.; Bruce, A.T.; White, J.M.; Swanson, P.E.; Old, L.J.; Schreiber, R.D. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature, 2001, 410(6832), 1107-1111.
65. [65] Pardoll, D. Does the immune system see tumors as foreign or self? Annu. Rev. Immunol., 2003, 21, 807-839.
66. [66] Smyth, M.J.; Dunn, G.P.; Schreiber, R.D. Cancer immunosurveillance and immunoediting: The roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv. Immunol., 2006, 90, 1-50.
67. [67] Smyth, M.J.; Swann, J.; Cretney, E.; Zerafa, N.; Yokoyama, W.M.; Hayakawa, Y. NKG2D function protects the host from tumor initiation. J. Exp. Med., 2005, 202(5), 583-588.
68. [68] Dunn, G.P.; Bruce, A.T.; Ikeda, H.; Old, L.J.; Schreiber, R.D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol., 2002, 3(11), 991-998.
69. [69] Dunn, G.P.; Old, L.J.; Schreiber, R.D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity, 2004, 21(2), 137-148.
70. [70] Dunn, G.P.; Old, L.J.; Schreiber, R.D. The three Es of cancer immunoediting. Annu. Rev. Immunol., 2004, 22, 329-360.
71. [71] Nicolini, A.; Carpi, A. Immune manipulation of advanced breast cancer: an interpretative model of the relationship between immune system and tumor cell biology. Med. Res. Rev., 2009, 29(3), 436-471.
72. [72] Carpi, A.; Nicolini, A.; Antonelli, A.; Ferrari, P.; Rossi, G. Cytokines in the management of high risk or advanced breast cancer: an update and expectation. Curr. Cancer Drug Targets, 2009, 9(8), 888-903.
73. [73] Nicolini, A.; Carpi, A.; Ferrari, P.; Berti, P.; Miccoli, P. Microenvironment and cytokines in breast cancer. In: Breast cancer: from pathogenesis to potential therapeutic modalities. Adit Ben Baruch editor, Transworld Research Network, Kerala, India, 2009, chapter 5, 107-163.
74. [74] Croci, D.O.; Zacarías, Fluck M.F.; Rico, M.J.; Matar, P.; Rabinovich, G.A.; Scharovsky, O.G. Dynamic cross-talk between tumor and immune cells in orchestrating the immunosuppressive network at the tumor microenvironment. Cancer Immunol. Immunother., 2007, 56(11), 1687-700.
75. [75] Paik, S.; Shak, S.; Tang, G.; Kim, C.; Baker, J.; Cronin, M.; Baehner, F.L.; Walker, M.G.; Watson, D.; Park, T.; Hiller, W.; Fisher, E.R.; Wickerham, D.L.; Bryant, J.; Wolmark, N. A multigene assay to predict recurrence of tamoxifen-treated, nodenegative breast cancer. N. Engl. J. Med., 2004, 351(27), 2817-2826.
76. [76] Hoskins, J.M.; Carey, L.A.; McLeod, H.L. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat. Rev. Cancer, 2009, 9(8), 576-586.
77. [77] Fu X.; Osborne C.K.; Schiff R. Biology and therapeutic potential of PI3K signaling in ER+/HER2-negative breast cancer. Breast, 2013, 22(Suppl 2), S12-18.
78. [78] Paplomata, E.; Zelnak, A.; O'Regan, R. Everolimus: side effect profile and management of toxicities in breast cancer. Breast Cancer Res Treat. 2013, 140(3), 453-462.
79. [79] Dedeurwaerder, S.; Desmedt, C.; Calonne, E.; Singhal, S.K.; Haibe-Kains, B.; Defrance, M.; Michiels, S.; Volkmar, M.; Deplus, R.; Luciani, J.; Lallemand, F.; Larsimont, D.; Toussaint, J.; Haussy, S.; Rothé, F.; Rouas, G.; Metzger, O.; Majjaj, S.; Saini, K.; Putmans, P.; Hames, G.; van Baren, N.; Coulie, P.G.; Piccart, M.; Sotiriou, C.; Fuks, F. DNA methylation profiling reveals a predominant immune component in breast cancers. EMBO Mol. Med., 2011, 3(12), 726-741.
80. [80] Ohaegbulam, K.C.; Assal, A.; Lazar-Molnar, E.; Yao, Y.; Zang, X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol. Med., 2015, 21(1), 24-33.
81. [81] Ali, K.; Soond, D.R.; Piñeiro, R.; Hagemann, T.; Pearce, W.; Lim, E.L.; Bouabe, H.; Scudamore, C.L.; Hancox, T.; Maecker, H.; Friedman, L.; Turner, M.; Okkenhaug, K.; Vanhaesebroeck, B. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature, 2014, 510(7505), 407-411.
82. [82] Vignon, F.; Bouton, M.M.; Rochefort, H. Antiestrogens inhibit the mitogenic effect of growth factors on breast cancer cells in the total absence of estrogens. Biochem. Biophys. Res. Commun., 1987, 146(3), 1502-1508.
83. [83] Wolf, D.M.; Gottardis, M.M.; Jordan, V.C. Tamoxifen-resistant growth. In: Long-term tamoxifen treatment for breast cancer; Jor dan, V.C., ed. Madison: The University of Wisconsin Press; 1994, pp.199-217.
84. [84] Nicolini, A.; Carpi, A. Beta-interferon and interleukin-2 prolong more than three times the survival of 26 consecutive endocrine dependent breast cancer patients with distant metastases: an exploratory trial. Biomed. Pharmacother., 2005, 59(5), 253-263.
85. [85] Nicolini, A.; Carpi, A.; Rossi, G. Relationship of cellular immunity, cytokines and CRP with clinical course in breast cancer patients with endocrine-dependent distant metastases treated with immunotherapy. Cancer Lett., 2007, 251(2), 330-338.
86. [86] Nicolini, A.; Rossi, G.; Ferrari, P.; Carpi, A. Clinical and laboratory patterns during immune stimulation in hormone responsive metastatic breast cancer. Biomed Pharmacother., 2014, 68(2), 171-178.
87. [87] Recchia, F.; Frati, L.; Rea, S.; Torchio, P.; Sica, G. Minimal residual disease in metastatic breast cancer: treatment with IFN-beta, retinoids, and tamoxifen. J. Interferon. Cytokine Res., 1998, 18(1), 41-47.
88. [88] Recchia, F.; Sica, G.; Candeloro, G.; Necozione, S.; Bisegna, R.; Bratta, M.; Rea, S. Maintenance immunotherapy in metastatic breast cancer. Oncol. Rep., 2008, 20(5), 1173-1179.