Chemoprevention of Hormone Receptor-Negative Breast Cancer: New Approaches Needed

Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 188)


Results from clinical trials have demonstrated that it is possible to prevent estrogen-responsive breast cancers by targeting the estrogen receptor with selective estrogen receptor modulators (SERMs) (tamoxifen, raloxifene, or lasofoxifene) or with aromatase inhibitors (AIs) (anastrozole, letrozole, or exemestene). Results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective in preventing breast cancer than SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many ER-positive breast cancers, these drugs do not prevent ER-negative breast cancer. These results show that new approaches are needed for the prevention of this aggressive form of breast cancer. Our laboratory and clinical efforts have been focused on identifying critical molecular pathways in breast cells that can be targeted for the prevention of ER-negative breast cancer. Our preclinical studies have demonstrated that other nuclear receptors, such as RXR receptors, vitamin D receptors, as well as others are critical for the growth of ER-negative breast cells and for the transformation of these cells into ER-negative cancers. Other studies show that growth factor pathways including those activated by EGFR, Her2, and IGFR, which are activated in many ER-negative breast cancers, can be targeted for the prevention of ER-negative breast cancer in mice. Clinical studies have also shown that PARP inhibitors are effective for the treatment of breast cancers arising in BRCA-1 or -2 mutation carriers, suggesting that targeting PARP may also be useful for the prevention of breast cancers arising in these high-risk individuals. Most recently, we have demonstrated that ER-negative breast cancers can be subdivided into four distinct groups based on the kinases that they express. These groups include ER-negative/Her-2-positive groups (the MAPK and immunomodulatory groups) and ER-negative/Her2-negative groups (the S6K and the cell cycle checkpoint groups). These groups of ER-negative breast cancers can be targeted with kinase inhibitors specific for each subgroup. These preclinical studies have supported the development of several clinical trials testing targeted agents for the prevention of breast cancer. The results of a completed Phase II cancer prevention trial using the RXR ligand bexarotene in women at high risk of breast cancer will be reviewed, and the current status of an ongoing Phase II trial using the EGFR and Her2 kinase inhibitor lapatinib for the treatment of women with DCIS breast cancer will be presented. It is anticipated that in the future these molecularly targeted drugs will be combined with hormonal agents such as SERMs or aromatase inhibitors to prevent all forms of breast cancer.


Breast Cancer Aromatase Inhibitor PARP Inhibitor Selective Estrogen Receptor Modulator Lipophilic Statins 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Anzano MA, Byers SW et al (1994) Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single agent and in combination with tamoxifen. Cancer Res 54(17):4614–4617PubMedGoogle Scholar
  2. Ariga R, Zarif A et al (2005) Correlation of her-2/neu gene amplification with other prognostic and predictive factors in female breast carcinoma. Breast J 11(4):278–280PubMedCrossRefGoogle Scholar
  3. Bailey CJ, Turner RC (1996) Metformin. N Engl J Med 334(9):574–579PubMedCrossRefGoogle Scholar
  4. Bonovas S, Filioussi K et al (2005) Use of statins and breast cancer: a meta-analysis of seven randomized clinical trials and nine observational studies. J Clin Oncol 23(34):8606–8612PubMedCrossRefGoogle Scholar
  5. Bryant HE, Schultz N et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913–917PubMedCrossRefGoogle Scholar
  6. Campbell MJ, Esserman LJ et al (2006) Breast cancer growth prevention by statins. Cancer Res 66(17):8707–8714PubMedCrossRefGoogle Scholar
  7. Cazzaniga M, Bonanni B et al (2009) Is it time to test metformin in breast cancer clinical trials? Cancer Epidemiol Biomarkers Prev 18(3):701–705PubMedCrossRefGoogle Scholar
  8. Chan KC, Knox WF et al (2001) Blockade of growth factor receptors in ductal carcinoma in situ inhibits epithelial proliferation. Br J Surg 88(3):412–418PubMedCrossRefGoogle Scholar
  9. Chlebowski R, Cuzick J et al (2009) Clinical perspectives on the utility of aromatase inhibitors for the adjuvant treatment of breast cancer. Breast 18(Suppl 2):S1–11PubMedCrossRefGoogle Scholar
  10. Clay CE, Namen AM et al (1999) Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells. Carcinogenesis 20(10):1905–1911PubMedCrossRefGoogle Scholar
  11. Cummings SR, Eckert S et al (1999) The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple outcomes of raloxifene evaluation. Jama 281(23):2189–2197PubMedCrossRefGoogle Scholar
  12. Cummings SR, Ensrud K et al (2010) “Lasofoxifene in postmenopausal women with osteoporosis.” N Engl J Med 362(8): 686-96.PubMedCrossRefGoogle Scholar
  13. Cuzick J (2003). Aromatase inhibitors in prevention – data from the ATAC (arimidex, tamoxifen alone or in combination) trial and the design of IBIS-II (the second International Breast Cancer Intervention Study). Recent Results Cancer Res 163:96–103; discussion 264–266Google Scholar
  14. Cuzick J (2008) IBIS II: a breast cancer prevention trial in postmenopausal women using the aromatase inhibitor anastrozole. Expert Rev Anticancer Ther 8(9):1377–1385PubMedCrossRefGoogle Scholar
  15. Cuzick J, Baum M (1985) Tamoxifen and contralateral breast cancer. Lancet 2(8449):282PubMedCrossRefGoogle Scholar
  16. Cuzick J, Forbes JF et al (2007) Long-term results of tamoxifen prophylaxis for breast cancer–96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 99(4):272–282PubMedCrossRefGoogle Scholar
  17. Cuzick J, Powles T et al (2003) Overview of the main outcomes in breast-cancer prevention trials. Lancet 361(9354):296–300PubMedCrossRefGoogle Scholar
  18. Dannenberg AJ, Lippman SM et al (2005) Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 23(2):254–266PubMedCrossRefGoogle Scholar
  19. Dearth RK, Delgado DA et al (2010) Parity-induced decrease in systemic growth hormone alters mammary gland signaling: A potential role in pregnancy protection from breast cancer. Cancer Preve Res (Phila Pa) 3(3):312–321CrossRefGoogle Scholar
  20. Dunn BK, Ryan A (2009) Phase 3 trials of aromatase inhibitors for breast cancer prevention: following in the path of the selective estrogen receptor modulators. Ann N Y Acad Sci 1155:141–161PubMedCrossRefGoogle Scholar
  21. Fisher B, Costantino JP et al (2005) Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 97(22):1652–1662PubMedCrossRefGoogle Scholar
  22. Fisher B, Costantino JP et al (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90(18):1371–1388PubMedCrossRefGoogle Scholar
  23. Fong PC, Boss DS et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2): 123–134PubMedCrossRefGoogle Scholar
  24. Forbes JF, Cuzick J et al (2008) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 9(1):45–53PubMedCrossRefGoogle Scholar
  25. Garwood ER, Kumar AS et al (2010) “Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer.” Breast Cancer Res Treat 119(1): 137-44.PubMedCrossRefGoogle Scholar
  26. Giardiello FM, Brensinger JD et al (2000) Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119(6):1447–1453PubMedCrossRefGoogle Scholar
  27. Goodwin PJ (2008) Insulin in the adjuvant breast cancer setting: a novel therapeutic target for lifestyle and pharmacologic interventions? J Clin Oncol 26(6):833–834PubMedCrossRefGoogle Scholar
  28. Goodwin PJ, Ligibel JA et al (2009) Metformin in breast cancer: time for action. J Clin Oncol 27(20):3271–3273PubMedCrossRefGoogle Scholar
  29. Goss PE, Richardson H et al (2007) National Cancer Institute of Canada Clinical Trials Group MAP.3 Trial: evaluation of exemestane to prevent breast cancer in postmenopausal women. Clin Breast Cancer 7(11):895–900PubMedCrossRefGoogle Scholar
  30. Harris RE, Alshafie GA et al (2000) Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res 60(8): 2101–2103PubMedGoogle Scholar
  31. Hong WK, Lippman SM et al (1990) Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323(12):795–801PubMedCrossRefGoogle Scholar
  32. Honig SF (2001) Tamoxifen for the reduction in the incidence of breast cancer in women at high risk for breast cancer. Ann N Y Acad Sci 949:345–348PubMedCrossRefGoogle Scholar
  33. Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse SF, Feuer EJ, Huang L, Mariotto A, Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, Edwards BK (eds) (2009). SEER Cancer Statistics Review, 1975–2006. Retrieved July 15, 2009, 2009, from, Scholar
  34. Howe LR, Subbaramaiah K et al (2002) Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res 62(19):5405–5407PubMedGoogle Scholar
  35. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5(5):341–354PubMedCrossRefGoogle Scholar
  36. Ip MM, Masso-Welch PA et al (1999) Conjugated linoleic acid inhibits proliferation and induces apoptosis of normal rat mammary epithelial cells in primary culture. Exp Cell Res 250(1):22–34PubMedCrossRefGoogle Scholar
  37. Josefsson ML, Leinster SJ (2010) “Aromatase inhibitors versus tamoxifen as adjuvant hormonal therapy for oestrogen sensitive early breast cancer in postmenopausal women: Meta-analyese of monotherapy, sequenced therapy and extended therapy.” Breast. Google Scholar
  38. Khuder SA, Mutgi AB (2001) Breast cancer and NSAID use: a meta-analysis. Br J Cancer 84(9):1188–1192PubMedCrossRefGoogle Scholar
  39. Kleinberg DL, Wood TL et al (2009) Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions. Endocr Rev 30(1):51–74PubMedCrossRefGoogle Scholar
  40. Kong G, Kim HT et al (2005) The retinoid X receptor-selective retinoid, LGD1069, down-regulates cyclooxygenase-2 expression in human breast cells through transcription factor crosstalk: implications for molecular-based chemoprevention. Cancer Res 65(8):3462–3469PubMedGoogle Scholar
  41. Kumar AP, Quake AL et al (2009) Repression of NHE1 expression by PPARgamma activation is a potential new approach for specific inhibition of the growth of tumor cells in vitro and in vivo. Cancer Res 69(22):8636–8644PubMedCrossRefGoogle Scholar
  42. Kumar AS, Benz CC et al (2008) Estrogen receptor-negative breast cancer is less likely to arise among lipophilic statin users. Cancer Epidemiol Biomarkers Prev 17(5):1028–1033PubMedCrossRefGoogle Scholar
  43. Kumar AS, Campbell M et al (2006) A call for clinical trials: lipophilic statins may prove effective in treatment and prevention of particular breast cancer subtypes. J Clin Oncol 24(13):2127; author reply 2127–2128Google Scholar
  44. Larsson SC, Mantzoros CS et al (2007) Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 121(4):856–862PubMedCrossRefGoogle Scholar
  45. Lee HY, Dawson MI et al (1996) Retinoic acid receptor- and retinoid X receptor-selective retinoids activate signaling pathways that converge on AP-1 and inhibit squamous differentiation in human bronchial epithelial cells. Cell Growth Differ 7(8):997–1004PubMedGoogle Scholar
  46. Lerner LJ, Holthaus FJ Jr et al (1958) A non-steroidal estrogen antiagonist 1-(p-2-diethylaminoethoxyphenyl)-1-phenyl-2-p-methoxyphenyl ethanol. Endocrinology 63(3):295–318PubMedCrossRefGoogle Scholar
  47. Li Y, Zhang Y et al (2007) The Rexinoid LG100268 prevents the development of preinvasive and invasive estrogen receptor negative tumors in MMTV-erbB2 mice. Clin Cancer Res 13(20):6224–6231PubMedCrossRefGoogle Scholar
  48. Liby K, Rendi M et al (2006) The combination of the rexinoid, LG100268, and a selective estrogen receptor modulator, either arzoxifene or acolbifene, synergizes in the prevention and treatment of mammary tumors in an estrogen receptor-negative model of breast cancer. Clin Cancer Res 12(19):5902–5909PubMedCrossRefGoogle Scholar
  49. Liby K, Risingsong R et al (2008) Prevention and treatment of experimental estrogen receptor-negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl Ester and the rexinoid LG100268. Clin Cancer Res 14(14): 4556–4563PubMedCrossRefGoogle Scholar
  50. Litzenburger BC, Kim HJ et al (2009) BMS-536924 reverses IGF-IR-induced transformation of mammary epithelial cells and causes growth inhibition and polarization of MCF7 cells. Clin Cancer Res 15(1):226–237PubMedCrossRefGoogle Scholar
  51. Lu C, Speers C et al (2003) Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors. J Natl Cancer Inst 95(24):1825–1833PubMedCrossRefGoogle Scholar
  52. Maggiora M, Bologna M et al (2004) An overview of the effect of linoleic and conjugated-linoleic acids on the growth of several human tumor cell lines. Int J Cancer 112(6):909–919PubMedCrossRefGoogle Scholar
  53. Mason RP, Walter MF et al (2004) Effects of HMG-CoA reductase inhibitors on endothelial function: role of microdomains and oxidative stress. Circulation 109(21 Suppl 1):II34–41Google Scholar
  54. Medina D, Kittrell F et al (2009) Prevention of tumorigenesis in p53-null mammary epithelium by rexinoid bexarotene, tyrosine kinase inhibitor gefitinib, and celecoxib. Cancer Prev Res (Phila Pa) 2(2):168–174CrossRefGoogle Scholar
  55. Mehta RG, Williamson E et al (2000) A ligand of peroxisome proliferator-activated receptor gamma, retinoids, and prevention of preneoplastic mammary lesions. J Natl Cancer Inst 92(5):418–423PubMedCrossRefGoogle Scholar
  56. Moon RC, Thompson HJ et al (1979) N-(4-Hydroxyphenyl)retinamide, a new retinoid for prevention of breast cancer in the rat. Cancer Res 39(4):1339–1346PubMedGoogle Scholar
  57. Moulder SL, Yakes FM et al (2001) Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 61(24):8887–8895PubMedGoogle Scholar
  58. Mueck AO, Seeger H et al (2003) Effect of statins combined with estradiol on the proliferation of human receptor-positive and receptor-negative breast cancer cells. Menopause 10(4):332–336PubMedCrossRefGoogle Scholar
  59. Mueller E, Sarraf P et al (1998) Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell 1(3):465–470PubMedCrossRefGoogle Scholar
  60. Papa V, Belfiore A (1996) Insulin receptors in breast cancer: biological and clinical role. J Endocrinol Invest 19(5):324–333PubMedGoogle Scholar
  61. Powles TJ, Ashley S et al (2007) Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst 99(4):283–290PubMedCrossRefGoogle Scholar
  62. Rendi MH, Suh N et al (2004) The selective estrogen receptor modulator arzoxifene and the rexinoid LG100268 cooperate to promote transforming growth factor beta-dependent apoptosis in breast cancer. Cancer Res 64(10):3566–3571PubMedCrossRefGoogle Scholar
  63. Rigas B, Kashfi K (2005) Cancer prevention: a new era beyond cyclooxygenase-2. J Pharmacol Exp Ther 314(1):1–8PubMedCrossRefGoogle Scholar
  64. Salh B, Marotta A et al (1999) Investigation of the Mek-MAP kinase-Rsk pathway in human breast cancer. Anticancer Res 19(1B):731–740Google Scholar
  65. Savage DG, Antman KH (2002) Imatinib mesylate–a new oral targeted therapy. N Engl J Med 346(9):683–693PubMedCrossRefGoogle Scholar
  66. Sawyers CL, Hochhaus A et al (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99(10):3530–3539PubMedCrossRefGoogle Scholar
  67. Schreinemachers DM, Everson RB (1994) Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 5(2):138–146PubMedCrossRefGoogle Scholar
  68. Seewaldt VL, Kim JH et al (1997) All-trans-retinoic acid mediates G1 arrest but not apoptosis of normal human mammary epithelial cells. Cell Growth Differ 8(6):631–641PubMedGoogle Scholar
  69. Shaw RJ, Lamia KA et al (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310(5754):1642–1646PubMedCrossRefGoogle Scholar
  70. Strecker TE, Shen Q et al (2009) Effect of lapatinib on the development of estrogen receptor-negative mammary tumors in mice. J Natl Cancer Inst 101(2):107–113PubMedCrossRefGoogle Scholar
  71. Suh N, Wang Y et al (1999) A new ligand for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), GW7845, inhibits rat mammary carcinogenesis. Cancer Res 59(22):5671–5673PubMedGoogle Scholar
  72. Szanto A, Narkar V et al (2004) Retinoid X receptors: X-ploring their (patho)physiological functions. Cell Death Differ 11(Suppl 2):S126–143PubMedCrossRefGoogle Scholar
  73. Turini ME, DuBois RN (2002) Cyclooxygenase-2: a therapeutic target. Annu Rev Med 53:35–57PubMedCrossRefGoogle Scholar
  74. Tutt A et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. J Clin Oncol (Suppl) 27(18s): Abstr. CRA501Google Scholar
  75. Uray IP, Shen Q et al (2009) Rexinoid-induced expression of IGFBP-6 requires RARbeta-dependent permissive cooperation of retinoid receptors and AP-1. J Biol Chem 284(1):345–353PubMedCrossRefGoogle Scholar
  76. Vazquez-Martin A, Oliveras-Ferraros C et al (2009) The antidiabetic drug metformin: a pharmaceutical AMPK activator to overcome breast cancer resistance to HER2 inhibitors while decreasing risk of cardiomyopathy. Ann Oncol 20(3):592–595PubMedCrossRefGoogle Scholar
  77. Veronesi U, Maisonneuve P et al (2007) Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J Natl Cancer Inst 99(9):727–737PubMedCrossRefGoogle Scholar
  78. Vogel VG, Costantino JP et al (2006) Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295(23):2727–2741PubMedCrossRefGoogle Scholar
  79. Wendel M, Heller AR (2009) Anticancer actions of omega-3 fatty acids – current state and future perspectives. Anticancer Agents Med Chem 9(4):457–470PubMedCrossRefGoogle Scholar
  80. Woditschka S, Haag JD et al (2006) Neu-induced retroviral rat mammary carcinogenesis: a novel chemoprevention model for both hormonally responsive and nonresponsive mammary carcinomas. Cancer Res 66(13):6884–6891PubMedCrossRefGoogle Scholar
  81. Wolbach SB, Howe PR (1925) Tissue changes following deprivation of fat-soluble a vitamin. J Exp Med 42(6):753–777PubMedCrossRefGoogle Scholar
  82. Wu K, DuPre E et al (2006) Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade. Breast Cancer Res Treat 96(2):147–157PubMedCrossRefGoogle Scholar
  83. Wu K, Kim HT et al (2002a) Suppression of mammary tumorigenesis in transgenic mice by the RXR-selective retinoid, LGD1069. Cancer Epidemiol Biomarkers Prev 11(5):467–474PubMedGoogle Scholar
  84. Wu K, Kim HT et al (2000) 9-cis-Retinoic acid suppresses mammary tumorigenesis in C3(1)-simian virus 40 T antigen-transgenic mice. Clin Cancer Res 6(9):3696–3704PubMedGoogle Scholar
  85. Wu K, Zhang Y et al (2002b) The retinoid X receptor-selective retinoid, LGD1069, prevents the development of estrogen receptor-negative mammary tumors in transgenic mice. Cancer Res 62(22):6376–6380PubMedGoogle Scholar
  86. Xue F, Michels KB (2007) Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence. Am J Clin Nutr 86(3):s823–835PubMedGoogle Scholar
  87. Yang L, Ostrowski J et al (2001) The retinoic acid receptor antagonist, BMS453, inhibits normal breast cell growth by inducing active TGFbeta and causing cell cycle arrest. Oncogene 20(55):8025–8035PubMedCrossRefGoogle Scholar
  88. Yin F, Bruemmer D et al (2004) Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells. Oncogene 23(26):4614–4623PubMedCrossRefGoogle Scholar
  89. Yin F, Wakino S et al (2001) Troglitazone inhibits growth of MCF-7 breast carcinoma cells by targeting G1 cell cycle regulators. Biochem Biophys Res Commun 286(5):916–922PubMedCrossRefGoogle Scholar
  90. Zakikhani M, Dowling R et al (2006) Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66(21):10269–10273PubMedCrossRefGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of Clinical Cancer PreventionThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations