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Breast Cancer Research and Treatment

, Volume 116, Issue 1, pp 31–38 | Cite as

Biologic therapy of breast cancer: focus on co-inhibition of endocrine and angiogenesis pathways

  • Vivek RoyEmail author
  • Edith A. Perez
Review

Abstract

There remains a high unmet need for effective treatments for metastatic breast cancer. In recent years there have been many advances in the understanding of biological basis of cancer. Several cellular pathways have been identified that play crucial roles in causing or maintaining the cancer phenotype. Many new agents that target these pathways have entered the clinic or are being investigated. In order to improve the therapeutic efficacy seen with single-agent regimens, rational combinations of targeted agents are being evaluated in ongoing trials. The optimal sequencing and combination of agents has yet to be established. Endocrine and vascular endothelial growth factor pathways are the two most prominent pathways active in breast cancer cells and inhibition of either of these is associated with clinical benefit. Here we discuss the rationale for simultaneously targeting these pathways and highlight ongoing clinical trials.

Keywords

Breast cancer Angiogenesis Targeted therapies Clinical trial Aromatase inhibitor Sorafenib 

References

  1. 1.
    Jemal A, Siegel R, Ward E et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96. doi: 10.3322/CA.2007.0010 PubMedCrossRefGoogle Scholar
  2. 2.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108PubMedCrossRefGoogle Scholar
  3. 3.
    Gershanovich M, Chaudri HA, Campos D et al (1998) Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Ann Oncol 9(6):639–645. doi: 10.1023/A:1008226721932 PubMedCrossRefGoogle Scholar
  4. 4.
    Dombernowsky P, Smith I, Falkson G et al (1998) Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16(2):453–461PubMedGoogle Scholar
  5. 5.
    Kaufmann M, Bajetta E, Dirix LY et al (2000) Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 18(7):1399–1411PubMedGoogle Scholar
  6. 6.
    Nabholtz JM, Bonneterre J, Buzdar A, Robertson JF, Thurlimann B (2003) Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer 39(12):1684–1689. doi: 10.1016/S0959-8049(03)00326-5 PubMedCrossRefGoogle Scholar
  7. 7.
    Mouridsen H, Gershanovich M, Sun Y et al (2003) Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21(11):2101–2109. doi: 10.1200/JCO.2003.04.194 PubMedCrossRefGoogle Scholar
  8. 8.
    Bonneterre J, Buzdar A, Nabholtz JM et al (2001) Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer 92(9):2247–2258. doi:10.1002/1097-0142(20011101)92:9<2247::AID-CNCR1570>3.0.CO;2-YPubMedCrossRefGoogle Scholar
  9. 9.
    Nilsson S, Makela S, Treuter E et al (2001) Mechanisms of estrogen action. Physiol Rev 81(4):1535–1565PubMedGoogle Scholar
  10. 10.
    O’Lone R, Frith MC, Karlsson EK, Hansen U (2004) Genomic targets of nuclear estrogen receptors. Mol Endocrinol 18(8):1859–1875. doi: 10.1210/me.2003-0044 PubMedCrossRefGoogle Scholar
  11. 11.
    Losel R, Wehling M (2003) Nongenomic actions of steroid hormones. Nature Rev Mol Cell Biol 4(1):46–56. doi: 10.1038/nrm1009 CrossRefGoogle Scholar
  12. 12.
    Pietras RJ, Marquez-Garban DC (2007) Membrane-associated estrogen receptor signaling pathways in human cancers. Clin Cancer Res 13(16):4672–4676. doi: 10.1158/1078-0432.CCR-07-1373 PubMedCrossRefGoogle Scholar
  13. 13.
    Acconcia F, Ascenzi P, Bocedi A et al (2005) Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol. Mol Biol Cell 16(1):231–237. doi: 10.1091/mbc.E04-07-0547 PubMedCrossRefGoogle Scholar
  14. 14.
    Pietras RJ, Marquez DC, Chen HW, Tsai E, Weinberg O, Fishbein M (2005) Estrogen and growth factor receptor interactions in human breast and non-small cell lung cancer cells. Steroids 70(5–7):372–381. doi: 10.1016/j.steroids.2005.02.017 PubMedCrossRefGoogle Scholar
  15. 15.
    Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER (2007) A conserved mechanism for steroid receptor translocation to the plasma membrane. J Biol Chem 282(31):22278–22288. doi: 10.1074/jbc.M611877200 PubMedCrossRefGoogle Scholar
  16. 16.
    Marquez DC, Chen HW, Curran EM, Welshons WV, Pietras RJ (2006) Estrogen receptors in membrane lipid rafts and signal transduction in breast cancer. Mol Cell Endocrinol 246(1–2):91–100. doi: 10.1016/j.mce.2005.11.020 PubMedCrossRefGoogle Scholar
  17. 17.
    Song RX (2007) Membrane-initiated steroid signaling action of estrogen and breast cancer. Semin Reprod Med 25(3):187–197. doi: 10.1055/s-2007-973431 PubMedCrossRefGoogle Scholar
  18. 18.
    Kato S, Endoh H, Masuhiro Y et al (1995) Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270(5241):1491–1494. doi: 10.1126/science.270.5241.1491 PubMedCrossRefGoogle Scholar
  19. 19.
    Byrne AM, Bouchier-Hayes DJ, Harmey JH (2005) Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 9(4):777–794. doi: 10.1111/j.1582-4934.2005.tb00379.x PubMedCrossRefGoogle Scholar
  20. 20.
    Houston SJ, Plunkett TA, Barnes DM, Smith P, Rubens RD, Miles DW (1999) Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 79(7–8):1220–1226. doi: 10.1038/sj.bjc.6690196 PubMedCrossRefGoogle Scholar
  21. 21.
    Kolch W (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351(Pt 2):289–305. doi: 10.1042/0264-6021:3510289 PubMedCrossRefGoogle Scholar
  22. 22.
    Nicholson S, Sainsbury JR, Halcrow P, Chambers P, Farndon JR, Harris AL (1989) Expression of epidermal growth factor receptors associated with lack of response to endocrine therapy in recurrent breast cancer. Lancet 1(8631):182–185. doi: 10.1016/S0140-6736(89)91202-6 PubMedCrossRefGoogle Scholar
  23. 23.
    Johnston SR, Head J, Pancholi S et al (2003) Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. Clin Cancer Res 9(1 Pt 2):524S–532SPubMedGoogle Scholar
  24. 24.
    Shou J, Massarweh S, Osborne CK et al (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96(12):926–935PubMedCrossRefGoogle Scholar
  25. 25.
    Schneider BP, Miller KD (2005) Angiogenesis of breast cancer. J Clin Oncol 23(8):1782–1790. doi: 10.1200/JCO.2005.12.017 PubMedCrossRefGoogle Scholar
  26. 26.
    Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med 324(1):1–8PubMedGoogle Scholar
  27. 27.
    Foekens JA, Peters HA, Grebenchtchikov N et al (2001) High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res 61(14):5407–5414PubMedGoogle Scholar
  28. 28.
    Park JE, Keller GA, Ferrara N (1993) The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell 4(12):1317–1326PubMedGoogle Scholar
  29. 29.
    Mimura K, Kono K, Takahashi A, Kawaguchi Y, Fujii H (2007) Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2. Cancer Immunol Immunother 56(6):761–770. doi: 10.1007/s00262-006-0234-7 PubMedCrossRefGoogle Scholar
  30. 30.
    Clauss M, Gerlach M, Gerlach H et al (1990) Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med 172(6):1535–1545. doi: 10.1084/jem.172.6.1535 PubMedCrossRefGoogle Scholar
  31. 31.
    Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87(8):3336–3343PubMedGoogle Scholar
  32. 32.
    Gerber HP, McMurtrey A, Kowalski J et al (1998) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway: requirement for Flk-1/KDR activation. J Biol Chem 273(46):30336–30343. doi: 10.1074/jbc.273.46.30336 PubMedCrossRefGoogle Scholar
  33. 33.
    Rousseau S, Houle F, Landry J, Huot J (1997) p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 15(18):2169–2177. doi: 10.1038/sj.onc.1201380 PubMedCrossRefGoogle Scholar
  34. 34.
    Qi JH, Claesson-Welsh L (2001) VEGF-induced activation of phosphoinositide 3-kinase is dependent on focal adhesion kinase. Exp Cell Res 263(1):173–182. doi: 10.1006/excr.2000.5102 PubMedCrossRefGoogle Scholar
  35. 35.
    Weigand M, Hantel P, Kreienberg R, Waltenberger J (2005) Autocrine vascular endothelial growth factor signalling in breast cancer: evidence from cell lines and primary breast cancer cultures in vitro. Angiogenesis 8(3):197–204. doi: 10.1007/s10456-005-9010-0 PubMedCrossRefGoogle Scholar
  36. 36.
    Liang Y, Hyder SM (2005) Proliferation of endothelial and tumor epithelial cells by progestin-induced vascular endothelial growth factor from human breast cancer cells: paracrine and autocrine effects. Endocrinology 146(8):3632–3641. doi: 10.1210/en.2005-0103 PubMedCrossRefGoogle Scholar
  37. 37.
    Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276(13):9817–9824. doi: 10.1074/jbc.M010840200 PubMedCrossRefGoogle Scholar
  38. 38.
    Cristofanilli M, Valero V, Mangalik A et al. (2008) A phase II multicenter, double-blind, randomized trial to compare anastrozole plus gefinitib with anastrozole plus placebo in postmenopausal women with hormone receptor-positive (HR +) metastatic breast cancer (MBC). J Clin Oncol; 26(May 20 suppl): abstr 1012Google Scholar
  39. 39.
    Hyder SM, Huang JC, Nawaz Z et al (2000) Regulation of vascular endothelial growth factor expression by estrogens and progestins. Environ Health Perspect 108(5):785–790. doi: 10.2307/3454307 PubMedCrossRefGoogle Scholar
  40. 40.
    Morales DE, McGowan KA, Grant DS et al (1995) Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 91(3):755–763PubMedGoogle Scholar
  41. 41.
    Takei H, Lee ES, Jordan VC (2002) In vitro regulation of vascular endothelial growth factor by estrogens and antiestrogens in estrogen-receptor positive breast cancer. Breast Cancer 9(1):39–42. doi: 10.1007/BF02967545 PubMedCrossRefGoogle Scholar
  42. 42.
    Hyder SM, Nawaz Z, Chiappetta C, Stancel GM (2000) Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. Cancer Res 60(12):3183–3190PubMedGoogle Scholar
  43. 43.
    Ruohola JK, Valve EM, Karkkainen MJ, Joukov V, Alitalo K, Harkonen PL (1999) Vascular endothelial growth factors are differentially regulated by steroid hormones and antiestrogens in breast cancer cells. Mol Cell Endocrinol 149(1–2):29–40. doi: 10.1016/S0303-7207(99)00003-9 PubMedCrossRefGoogle Scholar
  44. 44.
    Garvin S, Nilsson UW, Huss FR, Kratz G, Dabrosin C (2006) Estradiol increases VEGF in human breast studied by whole-tissue culture. Cell Tissue Res 325(2):245–251. doi: 10.1007/s00441-006-0159-7 PubMedCrossRefGoogle Scholar
  45. 45.
    Lee JE, Chung KW, Han W et al (2004) Effect of estrogen, tamoxifen and epidermal growth factor on the transcriptional regulation of vascular endothelial growth factor in breast cancer cells. Anticancer Res 24(6):3961–3964PubMedGoogle Scholar
  46. 46.
    Ryden L, Jirstrom K, Bendahl PO et al (2005) Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer. J Clin Oncol 23(21):4695–4704. doi: 10.1200/JCO.2005.08.126 PubMedCrossRefGoogle Scholar
  47. 47.
    Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N Engl J Med 350(23):2335–2342. doi: 10.1056/NEJMoa032691 PubMedCrossRefGoogle Scholar
  48. 48.
    Liang Y, Brekken RA, Hyder SM (2006) Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr Relat Cancer 13(3):905–919. doi: 10.1677/erc.1.01221 PubMedCrossRefGoogle Scholar
  49. 49.
    Ryden L, Stendahl M, Jonsson H, Emdin S, Bengtsson NO, Landberg G (2005) Tumor-specific VEGF-A and VEGFR2 in postmenopausal breast cancer patients with long-term follow-up: implication of a link between VEGF pathway and tamoxifen response. Breast Cancer Res Treat 89(2):135–143. doi: 10.1007/s10549-004-1655-7 PubMedCrossRefGoogle Scholar
  50. 50.
    Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357(26):2666–2676. doi: 10.1056/NEJMoa072113 PubMedCrossRefGoogle Scholar
  51. 51.
    D. Miles D, Chan A, Romieu G et al. (2008) Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J Clin Oncol; 26(May 20 suppl) :abstr LBA1011Google Scholar
  52. 52.
    Miller KD, Chap LI, Holmes FA et al (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23(4):792–799. doi: 10.1200/JCO.2005.05.098 PubMedCrossRefGoogle Scholar
  53. 53.
    Traina T, Rugo H, Caravelli J et al (2006) Letrozole (L) with bevacizumab (B) is feasible in patients (pts) with hormone receptor-positive metastatic breast cancer (MBC). J Clin Oncol 24(18S):abstr 3050Google Scholar
  54. 54.
    Chow LQ, Eckhardt SG (2007) Sunitinib: from rational design to clinical efficacy. J Clin Oncol 25(7):884–896. doi: 10.1200/JCO.2006.06.3602 PubMedCrossRefGoogle Scholar
  55. 55.
    Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109. doi: 10.1158/0008-5472.CAN-04-1443 PubMedCrossRefGoogle Scholar
  56. 56.
    Burstein HJ, Elias AD, Rugo HS et al (2008) Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 26(11):1810–1816. doi: 10.1200/JCO.2007.14.5375 PubMedCrossRefGoogle Scholar
  57. 57.
    Bianchi G, Loibl S, Zamagni C et al. (2007) Phase II multicenter trial of sorafenib in the treatment of patients with metastatic breast cancer. ASCO Breast Cancer Symposium: Abstract 164Google Scholar
  58. 58.
    Moreno-Aspitia A, Morton RF, Hillman DW et al (2008) Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336. J Clin Oncol. doi: 10.1200/JCO.2007.15.5242 PubMedGoogle Scholar
  59. 59.
    Subramaniam DS, Wilkinson M, Liu M et al. (2008) Sorafenib in hormone-receptor positive (ER/PR+) metastatic breast cancer (MBC) resistant to aromatase inhibitors (AIs). ASCO Breast Cancer Symposium; Sept. 2008(Abstract 162)Google Scholar
  60. 60.
    Azad NS, Posadas EM, Kwitkowski VE et al (2008) Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26(22):3709–3714. doi: 10.1200/JCO.2007.10.8332 PubMedCrossRefGoogle Scholar
  61. 61.
    Microangiopathic Hemolytic Anemia (MAHA) in patients treated with Avastin® (bevacizumab) and sunitinib malate. FDA Medwatch 2008; posted July 14, 2008 http://www.fda.gov/medwatch/safety/2008/safety08.htm#Avastin (accessed August 30, 2008)

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  1. 1.Division of Hematology/OncologyMayo ClinicJacksonvilleUSA

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