The stressactivated mitogenactivated protein kinases JNK and p38

As stated above, significant influences on ER and AP-1 signaling may also occur following phosphorylation of the SAPK members Jun kinase (JNK) and p38. While the endpoints of such signaling are likely to be as diverse as for ERK1/2 MAP kinase, as stated above, significant in vitro associations with negative growth regulation in breast cancer cells have been reported for JNK and p38.16,17,53 If represented in clinical breast cancer, therefore, JNK and p38 signaling would perhaps be predicted to substantially impact on patient prognosis and endocrine response in a manner diametrically opposed to pMAP kinase. Again, our studies immunocytochemically employing phospho-specific antibodies for JNK and p38 in clinical breast cancer have proved interesting in this regard.128 We noted that nuclear activation of JNK or p38 was not uncommon within clinical breast cancer (Figure 10.3). Significant expression of activated p38 and JNK appeared to confer an advantage on duration of survival and endocrine response, an observation in marked contrast to our observations with pMAP kinase. This was particularly apparent within tumors where the relationship between response to endocrine therapy and elevated pMAP kinase activation proved imperfect. Thus, approximately 15% of objective respon-ders with elevated pMAP kinase activation in their tumors coexpressed activated JNK or p38.128 These data suggest that activation of p38 and JNK may serve as a "counterbalance" in some breast cancers for the undesirable positive influences of pMAP kinase, thereby facilitating the growth inhibitory activity of endocrine agents.129

However, our observations with SAPKs in clinical breast cancer remain controversial. Paradoxically, increases in both p38 and JNK activity have also been associated with disease progression with activity elevated in effusions compared with primary tumors and lymph node metastases, and p38 relating to reduced overall survival130 and to shortened progression-free survival in lymph node-positive breast cancer.131 Moreover, our preliminary studies also noted some increases in activity of both JNK and p38 at the time of disease relapse of ER-positive endocrine responsive clinical breast cancer when treated with tamoxi-fen. Increased JNK activity has similarly been measured by others in acquired tamoxifen-resistant clinical breast cancer,132,133 while Gutierrez et al85 reported that some ER-positive, acquired tamoxifen-resistant patients (and xenografts) show increased p38 activation alongside modest gains in HER2 amplification. The latter study also revealed strong correlations between ER, p38 and ERK, data cumulatively implying crosstalk between ER, HER2, p38 (and ERK) which contributes to tamoxifen-resistant growth. Indeed, evidence of such crosstalk has been demonstrated in a xenograft model of acquired tamoxifen-resis-tant MCF-7 cells.85 It is feasible that a positive role for stress-activated kinases such as p38 in driving clinical-resistant disease may occur via their regulation of AP-1 activity, which can also be increased in such material122,132,133 or perhaps via activation of ER or its coactivators to enhance agonism of the tamoxifen-ER

complex.85

THE FUTURE OF MITOGEN-ACTIVATED PROTEIN KINASE AS A THERAPEUTIC TARGET AND PROGNOSTIC MARKER

The clinical data described above regarding activation of ERK1/2 MAP kinase and the SAPKs JNK and p38 suggest that these signaling elements have prognostic potential. However, more definitive studies with greater access to appropriate clinical sample sets, including samples taken during response and at relapse, are required to confirm these initial findings. It should also be noted that this data may also have important therapeutic implications. For example, breast tumors derived from patients exhibiting de novo endocrine resistance and an unfavorable prognosis may be candidates for challenge with pharmacological agents disruptive of ERK1/2 MAP kinase signaling. The recent development of inhibitors of MEK1 activation,134,135 as well as further agents disruptive of the upstream erbB signaling network, notably including tyrosine kinase inhibitors such as "ZD1839/Iressa" and targeted antibody therapies such as Herceptin,136 could be valuable additions to the pharmacological armory appropriate in future management of the disease. Moreover, our observation that coexpression of activated JNK or p38 in clinical breast cancer is associated with a perturbation of the relationship between phos-phorylated ERK 1/2 MAP kinase and poor outlook may ultimately provide some rationale for therapeutic manipulation of SAPKs to dampen any undesirable impact of elevated ERK 1/2 MAP kinase signaling. However, it should also be noted that the identification of a role for p38 and JNK in acquired tamoxifen resistance85,132,133 also identifies them, alongside ERK1/2 MAP kinase, as potential therapeutic targets for the treatment of this condition.

REFERENCES

1. Seery LT, Gee JMW, Dewhurst OL et al. Molecular mechanisms of antiestrogen action. In: Oettel M, Schillinger E, eds. Pharmacological Handbook. Berlin: Springer-Verlag, 1999: 201-20.

2. Nicholson RI, Manning DL, Gee JMW. New antihormonal approaches to breast cancer therapy. Drugs of Today 1993; 29: 363-72.

3. Nicholson RI, McClelland RA, Robertson JFR et al. Involvement of steroid hormone and growth factor cross-talk in endocrine response in breast cancer. Endocr Rel Cancer 1999; 6: 373-87.

4. Nicholson RI, Gee JWM. Oestrogen and growth factor cross-talk and endocrine insensitivity and acquired resistance in breast cancer. Br J Cancer 2000; 82: 501-13.

5. Widmann C, Gibson S, Jarpe MB et al. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 1999; 79(1): 143-80.

6. Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 2001; 81(2): 807-69.

7. Dhillon AS, Hagan S, Rath O et al. MAP kinase signalling pathways in cancer. Oncogene 2007; 26: 3279-90.

8. Schlessinger J. Cell signalling by receptor tyrosine kinases. Cell 2000; 103: 211-25.

9. Turjanski AG, Vaque JP, Gutkind JS. MAP kinases and the control of nuclear events. Oncogene 2007; 26: 3240-53.

10. Meloche S, Pouyssegur J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 2007; 26: 3227-39.

11. Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 2006; 24: 21-44.

12. Wang X, Tournier C. Regulation of cellular functions by the ERK5 signalling pathway. Cell Signal 2006; 18: 753-60.

13. Bagrodia S, Derijard B, Davis RJ et al. Cdc42 and PAK-mediated signalling leads to Jun kinase and p38 mitogen-activated protein kinase activation. J Biol Chem 1995; 270(47): 27,995-8.

Yuasa T, Ohno S, Kehrl JH et al. Tumour necrosis factor signalling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. J Biol Chem 1998; 273(35): 22,681-92.

Fanger GR, Johnson NL, Johnson GL. MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42. EMBO J 1997; 16(16): 4961-72. Zarubin T, Han J. Activation and signalling of the p38 MAP kinase pathway. Cell Res 2005; 15: 11-18. Weston CR, Davis RJ. The JNK signal transduction pathway. Curr Opin Cell Biol 2007; 19: 142-9. Robertson JF, Williams MR, Todd J et al. Factors predicting the response of patients with advanced breast cancer to endocrine (Megace) therapy. Eur J Cancer Clin Oncol 1989; 25: 469-75. Nicholson RI, Bouzubar N, Walker KJ et al. Hormone sensitivity in breast cancer: influence of heterogeneity of oestrogen receptor expression and cell proliferation. Eur J Cancer 1991; 27: 908-13.

Locker AP, Birrell K, Bell JA et al. Ki67 immunore-activity in breast carcinoma: relationships to prognostic variables and short term survival. Eur J Surg Oncol 1992; 18: 224-9.

Nicholson RI, Wilson DW, Richards G et al. Biological and clinical aspects of oestrogen receptor measurements in rapidly progressing breast cancer. In: Paton W, Mitchell J, Turner P, eds. Proceedings of the IUPHAR 9th International Congress of Pharmacology. Volume 3. London: McMillan Press, 1984: 75-9.

Kushner PJ, Agard DA, Greene GL et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 2000; 74: 311-17.

Aronica SM, Katzenellenbogen BS. Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the ratuterine estrogen receptor by estrogen, cyclic adenosinemono-phosphate, and insulin-like growth factor-I. Mol Endocrinol 1993; 7(6): 743-52. Bunone G, Briand PA, Miksicek RJ et al. Activation of the unliganded estrogen receptor by EGF involves the MAP k pathway and direct phosphory-lation. EMBO J 1996; 15: 2174-83. Pietras RJ, Arboleda J, Reese DM et al. HER-2 tyro-sine k pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 1995; 10: 2435-46. Lee AV, Weng CN, Jackson JG et al. Activation of estrogen receptor-mediated gene transcription by IGF-I in human breast cancer cells. J Endocrinol 1997; 152(1): 39-47.

Ignar-Trowbridge DM, Pimentel M, Parker MG et al. Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein k C or estradiol. Endocrinology 1996; 137(5): 1735-44.

28. Joel PB, Smith J, Sturgill TW et al. pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Mol Cell Biol 1998; 18: 1978-84.

29. Kato S, Endoh H, Masuhiro Y et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 1995; 270: 1491-94.

30. Lannigan DA. Estrogen receptor phosphorylation. Steroids 2003; 68: 1-9.

31. Likhite VS, Stossi F, Kim K et al. Kinase-specific phosphorylation of the estrogen receptor changes receptor interactions with ligand, deoxyribonucleic acid, and coregulators associated with alterations in estrogen and tamoxifen activity. Mol Endocrinol 2006; 20: 3120-32.

32. Weigel NL, Moore NL. Kinases and protein phos-phorylation as regulators of steroid hormone action. Nucl Recept Signal 2007; 5: e005.

33. Lee H, Bai W. Regulation of estrogen receptor nuclear export by ligand-induced and p38-medi-ated receptor phosphorylation. Mol Cell Biol 2002; 22: 5835-45.

34. Takahashi T, Ohmichi M, Kawagoe J et al. Growth factors change nuclear distribution of estrogen receptor-alpha via mitogen-activated protein kinase or phosphatidylinositol 3-kinase cascade in a human breast cancer cell line. Endocrinology 2005; 146: 4082-9.

35. Yang Z, Barnes CJ, Kumar R. Human epidermal growth factor receptor 2 status modulates subcellu-lar localization of and interaction with estrogen receptor alpha in breast cancer cells. Clin Cancer Res 2004; 10: 3621-8.

36. Le Goff P, Montano MM, Schodin DJ et al. Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. J Biol Chem 1994; 269: 4458-66.

37. Feng W, Webb P, Nguyen P et al. Potentiation of estrogen receptor activation function 1 (AF-1) by Src/JNK through a serine 118-independent pathway. Mol Endocrinol 2001; 15: 32-45.

38. McDonnell DP, Dana SL, Hoener PA et al. Cellular mechanisms which distinguish between hormone-and antihormone-activated estrogen receptor. Ann N Y Acad Sci 1995; 761: 121-37.

39. Oh AS, Lorant LA, HollowayJN et al. Hyper-activation of MAPK induces loss of ERalpha expression in breast cancer cells. Mol Endocrinol 2001; 15: 1344-59.

40. Creighton CJ, Hilger AM, Murthy S et al. Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors. Cancer Res 2006; 66: 3903-11.

41. Henrich LM, Smith JA, Kitt D et al. Extracellular signal-regulated kinase 7, a regulator of hormone-dependent estrogen receptor destruction. Mol Cell Biol 2003; 23: 5979-88.

42. Kronblad A, Hedenfalk I, Nilsson E et al. ERK1/2 inhibition increases antiestrogen treatment efficacy by interfering with hypoxia-induced downregulation of ERalpha: a combination therapy potentially targeting hypoxic and dormant tumour cells. Oncogene 2005; 24: 6835-41.

43. Holloway JN, Murthy S, El-Ashry D. A cytoplasmic substrate of mitogen-activated protein kinase is responsible for estrogen receptor-alpha down-regulation in breast cancer cells: the role of nuclear fac-tor-kappaB. Mol Endocrinol 2004; 18: 1396-410.

44. Nicholson RI, Gee JWM. Growth factors and modulation of endocrine response in breast cancer. In: Vedeckis WV, ed. Hormones and Cancer. Boston: Birkhauser, 1996: 227-61.

45. Gee JWM, McClelland RA, Nicholson RI. Growth factors and endocrine sensitivity in breast cancer. In: Pasqualini JR, Katzenellenbogen BS, eds. Molecular and Clinical Endocrinology. Marcel Dekker Publishing, 1996: 169-97.

46. Bates SE, Davidson NE, Valverius EM et al. Expression of transforming growth factor-alpha and its mRNA in human breast cancer: its regulation by oestrogen and its possible functional significance. Mol Endocrinol 1988; 2: 543-55.

47. Berthois Y, Dong XF, Martin PM. Regulation of epidermal growth factor receptor by oestrogen and antioestrogen in the human breast cancer cell line MCF-7. Biochem Biophys Res Commun 1989; 159: 126-31.

48. Hamelers IH, Steenbergh PH. Interactions between estrogen and insulin-like growth factor signaling pathways in human breast tumor cells. Endocr Relat Cancer 2003; 10: 331-45.

49. Richards RG, DiAugustine RP, Petrusz P et al. Estradiol stimulates tyrosine phosphorylation of the insulin-like growth factor-1 receptor and insulin receptor substrate-1 in the uterus. Proc Natl Acad Sci USA 1996; 93: 12,002-7.

50. Nemere I, Pietras RJ, Blackmore PF. Membrane receptors for steroid hormones: signal transduction and physiological significance. J Cell Biochem 2003; 88: 438-45.

51. Levin ER, Pietras RJ. Estrogen receptors outside the nucleus in breast cancer. Breast Cancer Res Treat 2008; 108: 351-61.

52. Schiff R, Osborne CK. Endocrinology and hormone therapy in breast cancer: new insight into estrogen receptor-alpha function and its implication for endocrine therapy resistance in breast cancer. Breast Cancer Res 2005; 7: 205-11.

53. Buck MB, Knabbe C. TGF-beta signalling in breast cancer. Ann NY Acad Sci 2006; 1089: 119-26.

54. Perry RR, Kang Y, Greaves BR. Relationship between tamoxifen-induced transforming growth factor beta

1 expression, cytostasis and apoptosis in human breast cancer cells. Br J Cancer 1995; 72: 1441-6.

55. Hill CS. Signalling to the nucleus by members of the transforming growth factor-beta (TGF-beta) superfamily. Cell Signal 1996; 8: 533-44.

56. Freiss G, Vignon F. Antiestrogens increase protein tyrosine phosphatase activity in human breast cancer cells. Mol Endocrinol 1994; 8: 1389-96.

57. Freiss G, Puech C, Vignon F. Extinction of insulinlike growth factor-I mitogenic signalling by anti-estrogen-stimulated Fas-associated protein tyrosine phosphatase-1 in human breast cancer cells. Mol Endocrinol 1998; 12: 568-79.

58. Gille H, Kortenjann M, Thomae O et al. ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO J 1995; 14: 951-62.

59. Eferl R, Wagner EF. AP-1: a double-edged sword in tumourigenesis. Nat Rev Cancer 2003; 3: 859-68.

60. Philips A, Chalbos D, Rochefort H. Estradiol increases and anti-estrogens antagonize the growth factor-induced activator protein-1 activity in MCF7 breast cancer cells without affecting c-fos and c-jun synthesis. J Biol Chem 1993; 268: 14,103-8.

61. Porter W, Saville B, Hoivik D et al. Functional synergy between the transcription factor Sp1 and the estrogen receptor. Mol Endocrinol 1997; 11: 1569-80.

62. Webb P, Lopez GN, Uht RM et al. Tamoxifen activation of the estrogen receptor/AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol Endocrinol 1995; 9: 443-56.

63. Nakshatri H, Bhat-Nakshatri P, Martin DA et al. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 1997; 17: 3629-39.

64. Sharma HW, Narayanan R. The NF-kappaB transcription factor in oncogenesis. Anticancer Res 1996; 16: 589-96.

65. Font de Mora J, Brown M. AIB1 is a conduit for kinase-mediated growth factor signalling to the estrogen receptor. Mol Cell Biol 2000; 20: 5041-7.

66. Rowan BG, Weigel NL, O'Malley BW. Phosphorylation of steroid receptor coactivator-1. Identification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway. J Biol Chem 2000; 275: 4475-83.

67. Lopez GN, Turck CW, Schaufele F et al. Growth factors signal to steroid receptors through mitogen-activated protein kinase regulation of p160 coactivator activity. J Biol Chem 2001; 276: 22,177-82.

68. Jonas BA, Privalsky ML. SMRT and N-CoR core-pressors are regulated by distinct kinase signalling pathways. J Biol Chem 2004; 279: 54,676-86.

69. Frigo DE, Basu A, Nierth-Simpson EN et al. p38 mitogen-activated protein kinase stimulates estrogen-mediated transcription and proliferation through the phosphorylation and potentiation of the p160 coactivator glucocorticoid receptor-interacting protein 1. Mol Endocrinol 2006; 20: 971-83. 83.

Zwijsen RM, Buckle RS, Hijmans EM et al. Ligand-independent recruitment of steroid receptor coac-tivators to estrogen receptor by cyclin D1. Genes Dev 1998; 12: 3488-98.

Kraus RJ, Ariazi EA, Farrell ML et al. Estrogen- 84. related receptor alpha 1 actively antagonizes estrogen receptor-regulated transcription in MCF-7 mammary cells. J Biol Chem 2002; 277: 24,826-34. Butt AJ, McNeil CM, Musgrove EA et al. Downstream 85. targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. Endocr Relat Cancer 2005; 12 (Suppl 1): S47-S59.

Morishita S, Niwa K, Ichigo S et al. Overexpressions of 86. c-fos/jun mRNA and their oncoproteins (Fos/Jun) in the mouse uterus treated with three natural estrogens. Cancer Lett 1995; 97: 225-31.

Mohamood AS, Gyles P, Balan KV et al. Estrogen 87. receptor, growth factor receptor and protooncogene protein activities and possible signal transduction crosstalk in estrogen dependent and independent breast cancer cell lines. J Submicrosc Cytol Pathol 88. 1997; 29: 1-17.

Dubik D, Shiu RP. Mechanism of estrogen activation of c-myc oncogene expression. Oncogene 1992; 7: 1587-94.

Lukas J, Bartkova J, Bartek J. Convergence of mito- 89. genic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent k-pRb-controlled G1 checkpoint. Mol Cell Biol 1996; 16: 6917-25.

Cohen BD, Siegall CB, Bacus S et al. Role of epi- 90. dermal growth factor receptor family members in growth and differentiation of breast carcinoma. Biochem Soc Symp 1998; 63: 199-210. Knowlden JM, Hutcheson IR, Jones HE et al. 91. Elevated levels of epidermal growth factor recep-tor/c-erbB2 heterodimers mediate an autocrine 92. growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 2003; 144: 1032-44. McClelland RA, Barrow D, Madden TA et al. Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term cul- 93. ture in the presence of the pure antiestrogen ICI 182,780 (Faslodex). Endocrinology 2001; 142: 2776-88.

Coutts AS, Murphy LC. Elevated mitogen-activated protein kinase activity in estrogen-nonresponsive 94. human breast cancer cells. Cancer Res 1998; 58: 4071-4.

Jeng MH, Yue W, Eischeid A et al. Role of MAP kinase in the enhanced cell proliferation of long- 95. term estrogen deprived human breast cancer cells. Breast Cancer Res Treat 2000; 62: 167-75. Donovan JCH, Milic A, Slingerland JM. Constitutive MEK/MAPK activation leads to p27Kip1 deregulation and antiestrogen resistance in human breast cancer cells. J Biol Chem 1997; 276: 40,888-95. Kurokawa H, Lenferink AEG, Simpson JF et al. Inhibition of HER/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen resistant breast cancer cells. Cancer Res 2000; 60: 5887-94. Cui Y, Parra I, Zhang M et al. Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: a mechanism of tamoxifen resistance. Cancer Res 2006; 66: 5950-59. Gutierrez MC, Detre S, Johnston S et al. Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 2005; 23: 2469-76.

Britton DJ, Hutcheson IR, Knowlden JM et al. Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res Treat 2006; 96: 131-46. Hutcheson IR, Knowlden JM, Madden TA et al. Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells. Breast Cancer Res Treat 2003; 81: 81-93. Lykkesfeldt AE, Mogens MW, Briand P. Altered expression of estrogen-regulated genes in a tamoxifen-resistant and ICI 164,384 and ICI 182,780 sensitive human breast cancer cell line, MCF-7/TAM R-1. Cancer Res 1994; 54: 1587-95.

Brunner N, Frandesen TL, Holst-Hansen C et al. MCF7/LCC2: a 4-hydroxytamoxifen resistant human breast cancer variant that retains sensitivity to the steroidal antiestrogen ICI 182,780. Cancer Res 1993; 53: 3229-32.

Johnston SR, Lu B, Dowsett M et al. Comparison of estrogen receptor DNA binding in untreated and acquired antiestrogen-resistant human breast tumors. Cancer Res 1997; 57: 3723-7.

Robertson JF. Oestrogen receptor: a stable pheno-type in breast cancer. Br J Cancer 1996; 73: 5-12. Martin LA, Farmer I, Johnston SR et al. Enhanced estrogen receptor (ER) alpha, ERBB2 and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term oestrogen deprivation. J Biol Chem 2003; 278: 30,458-68. Campbell RA, Bhat-Nakshatri P, Patel NM et al. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for antiestrogen resistance. J Biol Chem 2001; 276: 9817-24.

Shou J, Massarweh S, Osborne CK et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 2004; 96: 926-35. Chan CM, Martin LA, Johnston SR et al. Molecular changes associated with the acquisition of oestrogen hypersensitivity in MCF-7 breast cancer cells on long-term oestrogen deprivation. J Steroid Biochem Mol Biol 2002; 81: 333-41.

Vendrell JA, Bieche I, Desmetz C et al. Molecular changes associated with the agonist activity of hydroxy-tamoxifen and the hyper-response to estradiol in hydroxy-tamoxifen-resistant breast cancer cell lines. Endocr Relat Cancer 2005; 12: 75-92. Brodie A, Sabnis G, Jelovac D. Aromatase and breast cancer. J Steroid Biochem Mol Biol 2006; 102: 97-102.

Gibson MK, Nemmers LA, Beckman WC Jr et al. The mechanism of ICI 164,384 antiestrogenicity involves rapid loss of estrogen receptor in uterine tissue. Endocrinology 1991; 129: 2000-10. Dauvois S, Danielian PS, White R et al. Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover. Proc Natl Acad Sci USA 1992; 89: 4037-41.

Liang Y, Brekken RA, Hyder SM. Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr Relat Cancer 2006; 13: 905-19.

Thottassery JV, Sun Y, Westbrook L et al. Prolonged extracellular signal-regulated kinase 1/2 activation during fibroblast growth factor 1- or heregulin beta1-induced antiestrogen-resistant growth of breast cancer cells is resistant to mitogen-activated protein/extracellular regulated kinase kinase inhibitors. Cancer Res 2004; 64: 4637-47. Yue W, Fan P, Wang J et al. Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells. J Steroid Biochem Mol Biol 2007; 106: 102-10.

Gee JM, Robertson JF, Ellis IO et al. Phosphorylation of ERK1/2 mitogen-activated protein kinase is associated with poor response to antihormonal therapy and decreased patient survival in clinical breast cancer. Int J Cancer 2001; 95: 247-54.

Ueda S, Tsuda H, Sato K et al. Alternative tyrosine phosphorylation of signaling kinases according to hormone receptor status in breast cancer overex-pressing the insulin-like growth factor. Cancer Sci 2006; 97: 597-604.

Sivaraman VS, Wang H, Nuovo GJ et al. Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest 1997; 99: 1478-83.

Wang C, Thor AD, Moore DH 2nd et al. The overexpression of RHAMM, a hyaluronan-binding protein that regulates Ras signalling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression. Cancer Res 1998; 4: 567-76. Maemura M, Iino Y, Koibuchi Y et al. Mitogen-activated protein kinase cascade in breast cancer. Oncology 1999; 57: 37-44.

Salh B, Marotta A, Matthewson C et al. Investigation of the MEK-MAP kinase-Rsk pathway in human breast cancer. Anticancer Res 1999; 19: 731-40.

109. Mueller H, Flury N, Eppenberger-Castori S et al. Potential prognostic value of mitogen-activated protein kinase activity for disease-free survival of primary breast cancer patients. Int J Cancer (Pred Oncol) 2000; 89: 384-8.

110. Milde-Langosch K, Bamberger AM, Rieck G et al. Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer. Br J Cancer 2005; 92: 2206-15.

111. Nakopoulou L, Mylona E, Rafailidis P et al. Effect of different ERK2 protein localizations on prognosis of patients with invasive breast carcinoma. APMIS 2005; 113: 693-701.

112. Hoshino R, Chatani Y, Yamori T et al. Constitutive activation of the 41/43-kDa mitogen-activated protein kinase signalling pathway in human tumours. Oncogene 1999; 18: 813-22.

113. Gee JM, Robertson JF, Gutteridge E et al. Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer. Endocr Relat Cancer 2005; 12 (Suppl 1): S99-S111.

114. Giuliani R, Durbecq V, Di Leo A et al. Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC). Eur J Cancer 2007; 43: 725-35.

115. Baselga J, Albanell J, Ruiz A et al. Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 2005; 23: 5323-33.

116. Lehrer S, O'Shaughnessy J, Song HK et al. Activity of pp60c-src protein kinase in human breast cancer. Mt Sinai J Med 1989; 56: 83-5.

117. Yip SS, Crew AJ, Gee JM et al. Up-regulation of the protein tyrosine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression. Int J Cancer 2000; 88: 363-8.

118. Callans LS, Naama H, Khandelwal M et al. Raf-1 protein expression in human breast cancer cells. Ann Surg Oncol 1995; 2: 38-42.

119. Gordge PC, Hulme MJ, Clegg RA et al. Elevation of protein kinase A and protein kinase C activities in malignant as compared with normal human breast tissue. Eur J Cancer 1996; 32A: 2120-6.

120. Nicholson RI, McClelland RA, Finlay P et al. Relationship between EGF-R, c-erbB-2 protein expression and Ki67 immunostaining in breast cancer and hormone sensitivity. Eur J Cancer 1993; 29A: 1018-23.

121. Nicholson RI, McClelland RA, Gee JM et al. Transforming growth factor-alpha and endocrine sensitivity in breast cancer. Cancer Res 1994; 54: 1684-9.

122. Gee JM, Barroso AF, Ellis IO et al. Biological and clinical associations of c-jun activation in human breast cancer. Int J Cancer 2000; 89: 177-86.

123. Zhou JN, Ljungdahl S, Shoshan MC et al. Activation of tissue-factor gene expression in breast carcinoma cells by stimulation of the RAF-ERK signalling pathway. Mol Carcinog 1998; 21: 234-43.

124. Svensson S, Jirstrom K, Ryden L et al. ERK phosphorylation is linked to VEGFR2 expression and Ets-2 phosphorylation in breast cancer and is associated with tamoxifen treatment resistance and small tumours with good prognosis. Oncogene 2005; 24: 4370-9.

125. Sarwar N, Kim JS, Jiang J et al. Phosphorylation of ERalpha at serine 118 in primary breast cancer and in tamoxifen-resistant tumours is indicative of a complex role for ERalpha phosphorylation in breast cancer progression. Endocr Relat Cancer 2006; 13: 851-61.

126. Murphy LC, Niu Y, Snell L et al. Phospho-serine-118 estrogen receptor-alpha expression is associated with better disease outcome in women treated with tamoxifen. Clin Cancer Res 2004; 10: 5902-6.

127. Polychronis A, Sinnett HD, Hadjiminas D et al. Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor- receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomised trial. Lancet Oncol 2005; 6: 383-91.

128. Gee JM, Robertson JF, Ellis IO et al. Impact of activation of MAP kinase family members on endocrine response and survival in clinical breast cancer. Eur J Cancer 2000; 36 (Suppl 4): 105.

129. Zhang CC, Shapiro DJ. Activation of the p38 mitogen-activated protein kinase pathway by estrogen or by 4-hydroxytamoxifen is coupled to estrogen receptor-induced apoptosis. J Biol Chem 2000; 275: 479-86.

130. Davidson B, Konstantinovsky S, Kleinberg L et al. The mitogen-activated protein kinases (MAPK) p38 and JNK are markers of tumour progression in breast carcinoma. Gynecol Oncol 2006; 102: 453-61.

131. Esteva FJ, Sahin AA, Smith TL et al. Prognostic significance of phosphorylated P38 mitogen-activated protein kinase and HER-2 expression in lymph node-positive breast carcinoma. Cancer 2004; 100: 499-506.

132. Johnston SR, Lu B, Scott GK et al. Increased activator protein-1 DNA binding and c-Jun NH2-terminal kinase activity in human breast tumours with acquired tamoxifen resistance. Clin Cancer Res 1999; 5: 251-6.

133. Schiff R, Reddy P, Ahotupa M et al. Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumours in vivo. J Natl Cancer Inst 2000; 92: 1926-34.

134. Duesbery NS, Webb CP, Vande Woude GF. MEK wars, a new front in the battle against cancer. Nature Med 1999; 5: 736-7.

135. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 2004; 4: 937-47.

136. Slichenmyer WJ, Fry DW. Anticancer therapy targeting the erbB family of receptor tyrosine kinases. Semin Oncol 2001; 28: 67-79.

Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

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