Therapeutic targets in triple negative breast cancer

Journal of Clinical Pathology

Volumn 66, Issue 6, 2013, Pages 530-542

  O'Toole, Sandra A ^a,c   Beith, Jane M ^a,c   Millar, Ewan K A ^b,d,e,f   West, Richard ^a,c   McLean, Anna ^c   Cazet, Aurelie ^b   Swarbrick, Alexander ^b,d   Oakes, Samantha R ^b,d  

^a ROYAL PRINCE ALFRED HOSPITAL   (Australia)

^b GARVAN INSTITUTE OF MEDICAL RESEARCH   (Australia)

^c UNIVERSITY OF SYDNEY   (Australia)

^d UNIVERSITY OF NEW SOUTH WALES   (Australia)

^e ST GEORGE HOSPITAL   (Australia)

^f UNIVERSITY OF WESTERN SYDNEY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ANTHRACYCLINE; B LYMPHOCYTE RECEPTOR; B RAF KINASE; BETA CATENIN; BRCA1 PROTEIN; BUPARLISIB; CARBOPLATIN; CETUXIMAB; CISPLATIN; CYCLOPHOSPHAMIDE; EPIRUBICIN; FIBROBLAST GROWTH FACTOR RECEPTOR 1; FLUOROURACIL; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; ITRACONAZOLE; K RAS PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; METHOTREXATE; OLAPARIB; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN NOXA; SONIDEGIB; T LYMPHOCYTE RECEPTOR; TRASTUZUMAB; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND; UNINDEXED DRUG; VELIPARIB; WNT PROTEIN;

ACTIN FILAMENT; ADENOID CYSTIC CARCINOMA; ADJUVANT CHEMOTHERAPY; ANGIOGENESIS; ANTIGEN PRESENTATION; BLEEDING; BREAST CANCER; BREAST CARCINOMA; BREAST METASTASIS; CELL ADHESION; CELL DEATH; CELL DIVISION; CELL MOTILITY; DNA DAMAGE; DNA METHYLATION; DNA REPAIR; EMBRYONAL TISSUE; EPITHELIAL MESENCHYMAL TRANSITION; FEBRILE NEUTROPENIA; GENE MUTATION; GENOMIC INSTABILITY; HEALTH CARE QUALITY; HEART FAILURE; HEDGEHOG; HOMOLOGOUS RECOMBINATION; HUMAN; HYPERTENSION; IMMUNE RESPONSE GENE; IMMUNOHISTOCHEMISTRY; LYMPHATIC LEUKEMIA; META ANALYSIS; NEUROTOXICITY; NONHUMAN; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PRIMARY TUMOR; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEINURIA; REVIEW; RNA SEQUENCE; SINGLE NUCLEOTIDE POLYMORPHISM; SYSTEMIC THERAPY; TRIPLE NEGATIVE BREAST CANCER; TUMOR VIRUS; UNITED STATES; WNT SIGNALING PATHWAY;

BREAST CANCER; BREAST PATHOLOGY; CANCER RESEARCH;

ANGIOGENESIS INHIBITORS; ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; BREAST NEOPLASMS; FEMALE; HUMANS; MOLECULAR TARGETED THERAPY; RECEPTOR, ERBB-2; RECEPTORS, ESTROGEN; RECEPTORS, PROGESTERONE; SIGNAL TRANSDUCTION;

EID: 84878297133     PISSN: 00219746     EISSN: 14724146     Source Type: Journal    
DOI: 10.1136/jclinpath-2012-201361     Document Type: Review

References (182)

1. AIHW. Australian Institute of Health and Welfare & Cancer Australia 2012. Breast cancer in Australia: an overview. 2012; Cancer series no. 71(Cat. no. CAN 67. Canberra: AIHW.)
2. Arteaga CL, Sliwkowski MX, Osborne CK, et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 2012;9:16-32.
3. Smith CL, Kricker A, Armstrong BK. Breast cancer mortality trends in Australia: 1921 to 1994. Med J Aust 1998;168:11-14.
4. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Can Res 2007;13:2329-34.
5. Al-Hakeem DA, Fedele S, Carlos R, et al. Extranodal NK/T-cell lymphoma, nasal type. Oral Oncol 2007;43:4-14.
6. Badve S, Dabbs DJ, Schnitt SJ, et al. Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol 24:157-67.
7. Weigelt B, Mackay A, A'Hern R, et al. Breast cancer molecular profiling with single sample predictors: a retrospective analysis. Lancet Oncol 2010;11:339-49.
8. Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 2004;10:5367-74.
9. Hugh J, Hanson J, Cheang MC, et al. Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 2009;27:1168-76.
10. Fulford LG, Reis-Filho JS, Ryder K, et al. Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival. Breast Cancer Res 2007;9:R4.
11. Thike AA, Iqbal J, Cheok PY, et al. Triple negative breast cancer: outcome correlation with immunohistochemical detection of basal markers. Am J Surg Path 2010;34:956-64.
12. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med 2010;363:1938-48.
13. Brenton JD, Carey LA, Ahmed AA, et al. Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol 2005;23:7350-60.
14. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010;28:2784-95.
15. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007;13(15 Pt 1):4429-34.
16. Kennecke H, Yerushalmi R, Woods R, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol 2010;28:3271-7.
17. Kim JE, Ahn HJ, Ahn JH, et al. Impact of triple-negative breast cancer phenotype on prognosis in patients with stage I breast cancer. J Br Cancer 2012;15:197-202.
18. Plummer R. Poly(ADP-ribose) polymerase inhibition: a new direction for BRCA and triple-negative breast cancer? Br Cancer Res 2011;13:218.
19. Esteller M, Silva JM, Dominguez G, et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Instit 2000;92:564-9.
20. Osin P, Lu YJ, Stone J, et al. Distinct genetic and epigenetic changes in medullary breast cancer. Int J Surg Pathol 2003;11:153-8.
21. Prat A, Parker JS, Karginova O, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of Breast Cancer. Breast Cancer Res 2010;12:R68.
22. Desmedt C, Haibe-Kains B, Wirapati P, et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res 2008;14:5158-65.
23. Rodriguez AA, Makris A, Wu MF, et al. DNA repair signature is associated with anthracycline response in triple negative breast cancer patients. Breast Cancer Res Treat 2010;123:189-96.
24. Gucalp A, Traina TA. Triple-negative breast cancer: role of the androgen receptor. Cancer J 2010;16:62-5.
25. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:2750-67.
26. Farmer P, Bonnefoi H, Becette V, et al. Identi fication of molecular apocrine breast tumours by microarray analysis. Oncogene 2005;24:4660-71.
27. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012;486:395-9.
28. Cancer Atlas Genome Network. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70.
29. Coates AS, Millar EK, O'Toole SA, et al. Prognostic interaction between expression of p53 and estrogen receptor in patients with node-negative Breast Cancer: results from IBCSG Trials VIII and IX. Breast Cancer Res 2012;14:R143.
30. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6.
31. Banerji S, Cibulskis K, Rangel-Escareno C, et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 2012;486:405-9.
32. Robinson DR, Kalyana-Sundaram S, Wu YM, et al. Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nature Med 2011;17:1646-51.
33. Di Leo A, Desmedt C, Bartlett Jea. Final results of a meta-analysis testing HER2 and topoisomerase IIalpha genes as predictors of incremental benefit from anthracyclines in breast cancer. J Clin Oncol 2010;28(72s):Abstract 519.
34. Jacquemier J, Penault-Llorca F, al. MHe. dentification of a basal-like subtype and comparative effect of epirubicin-based chemotherapy andsequential epirubicin followed by docetaxel chemotherapy in the PACS 01 breast cancer trial: 33 markers studied on tissue-microarrays (TMA). J Clin Oncol 2006;24:(Abstr 509).
35. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008;26:1275-81.
36. Gonzalez-Angulo AM, Timms KM, Liu S, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clinical Cancer Res 2011;17:1082-9.
37. Frasci G, Comella P, Rinaldo M, et al. Preoperative weekly cisplatin-epirubicin-paclitaxel with G-CSF support in triple-negative large operable breast cancer. Ann Oncol 2009;20:1185-92.
38. Byrski T, Gronwald J, Huzarski T, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 2010;28:375-9.
39. Foulkes WD, Stefansson IM, Chappuis PO, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 2003;95:1482-5.
40. Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer 2004;4:814-19.
41. O'Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011;364:205-14.
42. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123-34.
43. Linderholm BK, Hellborg H, Johansson U, et al. Signi ficantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol 2009;20:1639-46.
44. Schutz FA, Jardim DL, Je Y, et al. Haematologic toxicities associated with the addition of bevacizumab in cancer patients. Eur J Cancer 2011;47:1161-74.
45. Choueiri TK, Mayer EL, Je Y, et al. Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol 2011;29:632-8.
46. Schutz FA, Je Y, Azzi GR, et al. Bevacizumab increases the risk of arterial ischemia: a large study in cancer patients with a focus on different subgroup outcomes. Ann Oncol 2011;22:1404-12.
47. von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 2012;366:299-309.
48. Bear H, Tang G, Rastogi Pea. The effect on pCR of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40. J Clin Oncol 2011;29:Abstr LBA 1005.
49. Teng YH, Tan WJ, Thike AA, et al. Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative Breast Cancer: possible implications for targeted therapy. Breast Can Res 2011;13:R35.
50. Jacot W, Lopez-Crapez E, Thezenas S, et al. Lack of EGFR-activating mutations in European patients with triple-negative Breast Cancer could emphasise geographic and ethnic variations in Breast Cancer mutation profiles. Breast Can Res 2011;13:R133.
51. Grob TJ, Heilenkotter U, Geist S, et al. Rare oncogenic mutations of predictive markers for targeted therapy in triple-negative breast cancer. Breast Can Res Treat 2012;134:561-7.
52. Viale G, Rotmensz N, Maisonneuve P, et al. Invasive ductal carcinoma of the breast with the 'triple-negative' phenotype: prognostic implications of EGFR immunoreactivity. Breast Cancer Res Treat 2009;116(2):317-28.
53. Baselga J, Stemmer S, Pego A, et al. Cetuximab plus cisplatin in estrogen receptor-negative, progesterone receptor-negative, HER2-negative (triplenegative) metastatic breast cancer: results of the randomized phase II BALI-1 trial. Cancer Res 2010;70:Abstr PD01-01.
54. Sharma P, Khan Q, Kimler Bea. Results of a phase II study of neoadjuvant platinum/taxane based chemotherapy and erlotinib for triple negative breast cancer. Cancer Res 2010;70:Abstr P1-11-07.
55. Bernsdorf M, Ingvar C, Jorgensen L, et al. Effect of adding gefitinib to neoadjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial. Breast Cancer Res Treat 2011;126:463-70.
56. Bader AG, Kang S, Zhao L, et al. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 2005;5:921-9.
57. Baselga J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist 2011;16(Suppl 1):12-19.
58. Lopez-Knowles E, O'Toole SA, McNeil CM, et al. PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specifi c mortality. Int J Cancer 2010;126:1121-31.
59. Marty B, Maire V, Gravier E, et al. Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like Breast Cancer cells. Breast Cancer Res Breast Can Res 2008;10:R101.
60. Fedele CG, Ooms LM, Ho M, et al. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc Natl Acad Sci 2010;107:22231-6.
61. Dourdin N, Schade B, Lesurf R, et al. Phosphatase and tensin homologue deleted on chromosome 10 deficiency accelerates tumor induction in a mouse model of ErbB-2 mammary tumorigenesis. Cancer Res 2008;68:2122-31.
62. Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to- mesenchymal transition and stem cell characteristics. Cancer Res 2009;69:4116-24.
63. Adamo B, Deal AM, Burrows E, et al. Phosphatidylinositol 3-kinase pathway activation in Breast Cancer brain metastases. Breast Cancer Res 2011;13:R125.
64. Yunokawa M, Koizumi F, Kitamura Y, et al. Efficacy of everolimus, a novel mTOR inhibitor, against basal-like triple-negative breast cancer cells. Cancer Sci 2012;103:1665-71.
65. Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, Balmañà J, Rajendran A, Papa A, Spencer K, Lyssiotis CA, Nardella C, Pandolfi PP, Baselga J, Scully R, Asara JM, Cantley LC, Wulf GM. Cancer Discov 2012;2(11):1048-63.
66. O'Toole SA, Swarbrick A, Sutherland RL. The Hedgehog signalling pathway as a therapeutic target in early breast cancer development. Expert Opin Ther Targets 2009;13:1095-103.
67. Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008;455:406-10.
68. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001;15:3059-87.
69. O'Toole SA, Machalek DA, Shearer RF, et al. Hedgehog overexpression is associated with stromal interactions and predicts for poor outcome in breast cancer. Cancer Res 2011;71:4002-14.
70. Li Y, Yang W, Yang Q, et al. Nuclear localization of GLI1 and elevated expression of FOXC2 in breast cancer is associated with the basal-like phenotype. Histol Histopathol 2012;27:475-84.
71. Harris LG, Pannell LK, Singh S, et al. Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61. Oncogene 2012;31:3370-80.
72. Lai D, Ho KC, Hao Y, et al. Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. Cancer Res 2011;71:2728-38.
73. Rijsewijk F, Schuermann M, Wagenaar E, et al. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell 1987;50:649-57.
74. Zeng YA, Nusse R. Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell stem cell 2010;6:568-77.
75. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004;303:1483-7.
76. Boutros M, Paricio N, Strutt DI, et al. Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling. Cell 1998;94:109-18.
77. King TD, Suto MJ, Li Y. The Wnt/beta-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer. J Cell Biol 2012;113:13-18.
78. Yang-Snyder J, Miller JR, Brown JD, et al. A frizzled homolog functions in a vertebrate Wnt signaling pathway. Current Biol 1996;6:1302-6.
79. Noordermeer J, Klingensmith J, Perrimon N, et al. dishevelled and armadillo act in the wingless signalling pathway in Drosophila. Nature 1994;367:80-3.
80. Izrailit J, Reedijk M. Developmental pathways in breast cancer and breast tumor-initiating cells: therapeutic implications. Cancer Lett 2012;317:115-26.
81. Eastman Q, Grosschedl R. Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Current Opin Cell Biol 1999;11:233-40.
82. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell 2006;127:469-80.
83. Geyer FC, Lacroix-Triki M, Savage K, et al. beta-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod Pathol 2011;24:209-31.
84. Hayes MJ, Thomas D, Emmons A, et al. Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast. Clinical Cancer Res 2008;14:4038-44.
85. Lacroix-Triki M, Geyer FC, Lambros MB, et al. beta-catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast. Mod Pathol 2010;23:1438-48.
86. Khramtsov AI, Khramtsova GF, Tretiakova M, et al. Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol 2010;176:2911-20.
87. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci 2003;100:3983-8.
88. Lopez-Knowles E, Zardawi SJ, McNeil CM, et al. Cytoplasmic localization of beta-catenin is a marker of poor outcome in breast cancer patients. Cancer Epidemiol Biomarkers Prev 2010;19:301-9.
89. Yang L, Wu X, Wang Y, et al. FZD7 has a critical role in cell proliferation in triple negative breast cancer. Oncogene 2011;30:4437-46.
90. Li Y, Welm B, Podsypanina K, et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci 2003;100:15853-8.
91. Ayyanan A, Civenni G, Ciarloni L, et al. Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. Proc Natl Acad Sci 2006;103:3799-804.
92. Teuliere J, Faraldo MM, Deugnier MA, et al. Targeted activation of beta-catenin signaling in basal mammary epithelial cells affects mammary development and leads to hyperplasia. Development 2005;132:267-77.
93. DeAlmeida VI, Miao L, Ernst JA, et al. The soluble wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo. Cancer Res 2007;67:5371-9.
94. Curtin JC, Lorenzi MV. Drug discovery approaches to target Wnt signaling in cancer stem cells. Oncotarget 2010;1:563-77.
95. Schreinemachers DM, Everson RB. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 1994;5:138-46.
96. Grosch S, Tegeder I, Niederberger E, et al. COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J 2001;15:2742-4.
97. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009;137:216-33.
98. Brou C, Logeat F, Gupta N, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 2000;5:207-16.
99. Mumm JS, Schroeter EH, Saxena MT, et al. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 2000;5:197-206.
100. Shah S, Lee SF, Tabuchi K, et al. Nicastrin functions as a gamma-secretase-substrate receptor. Cell 2005;122:435-47.
101. Gordon WR, Arnett KL, Blacklow SC. The molecular logic of Notch signaling - a structural and biochemical perspective. J Cell Sci 2008;121(Pt 19):3109-19.
102. Kovall RA. More complicated than it looks: assembly of Notch pathway transcription complexes. Oncogene 2008;27:5099-109.
103. Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 2003;194:237-55.
104. Guo S, Liu M, Gonzalez-Perez RR. Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim Biophys Acta 2011;1815:197-213.
105. Ling H, Sylvestre JR, Jolicoeur P. Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors. Oncogene 2010;29:4543-54.
106. Efstratiadis A, Szabolcs M, Klinakis A. Notch, Myc and breast cancer. Cell Cycle 2007;6:418-29.
107. Graziani I, Eliasz S, De Marco MA, et al. Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under hypoxia are exerted through the Akt pathway. Cancer Res 2008;68:9678-85.
108. Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 2004;279:2937-44.
109. Harrison H, Farnie G, Howell SJ, et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 2010;70:709-1.
110. Zardawi SJ, Zardawi I, McNeil CM, et al. High Notch1 protein expression is an early event in breast cancer development and is associated with the HER-2 molecular subtype. Histopathol 2010;56:286-96.
111. Reedijk M, Odorcic S, Chang L, et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 2005;65:8530-7.
112. Gonzalez-Angulo AM, Iwamoto T, Liu S, et al. Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer. Clinical Cancer Res 2012;18:1109-19.
113. Tsunoda Y, Sakamoto M, Sawada T, et al. Characteristic genes in luminal subtype breast tumors with CD44+CD24-/low gene expression signature. Oncology 2011;81:336-44.
114. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer 2005;5:275-84.
115. Pece S, Serresi M, Santolini E, et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 2004;167:215-21.
116. Rennstam K, McMichael N, Berglund P, et al. Numb protein expression correlates with a basal-like phenotype and cancer stem cell markers in primary breast cancer. Breast Cancer Res Treat 2010;122:315-24.
117. Lichtenthaler SF, Ida N, Multhaup G, et al. Mutations in the transmembrane domain of APP altering gamma-secretase specificity. Biochemistry 1997;36:15396-403.
118. Krop I, Demuth T, Guthrie T, et al. Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol 2012;30:2307-13.
119. Luistro L, He W, Smith M, et al. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res 2009;69:7672-80.
120. Rasul S, Balasubramanian R, Filipovic A, et al. Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells. Br J Cancer 2009;100:1879-88.
121. Zhang CC, Pavlicek A, Zhang Q, et al. Biomarker and Pharmacologic Evaluation of the gamma-Secretase Inhibitor PF-03084014 in Breast Cancer Models. Clin Cancer Res 2012;18:5008-19.
122. Lombardo Y, Filipovic A, Molyneux G, et al. Nicastrin regulates breast cancer stem cell properties and tumor growth in vitro and in vivo. Proc Natl Acad Sci 2012;109:16558-63.
123. McGowan PM, Simedrea C, Ribot EJ, et al. Notch1 inhibition alters the CD44hi/CD24lo population and reduces the formation of brain metastases from breast cancer. Mol Cancer Res 2011;9:834-44.
124. Sharma A, Paranjape AN, Rangarajan A, et al. A monoclonal antibody against human Notch1 ligand-binding domain depletes subpopulation of putative breast cancer stem-like cells. Mol Cancer Ther 2012;11:77-86.
125. Hoey T, Yen WC, Axelrod F, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell stem cell 2009;5:168-77.
126. Moellering RE, Cornejo M, Davis TN, et al. Direct inhibition of the NOTCH transcription factor complex. Nature 2009;462:182-8.
127. Parr C, Watkins G, Jiang WG. The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Int J Mol Med 2004;14:779-86.
128. Li H, Solomon E, Muggy S Duhachek, et al. Metalloprotease-disintegrin ADAM12 expression is regulated by Notch signaling via microRNA-29. J Biol Chem 2011;286:21500-10.
129. Li H, Duhachek-Muggy S, Qi Y, et al. An essential role of metalloprotease-disintegrin ADAM12 in triple-negative breast cancer. Breast Cancer Res Treat 2012;135:759-69.
130. Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol 2012;30:2615-23.
131. Seveno C, Loussouarn D, Brechet S, et al. gamma-secretase inhibition promotes cell death, Noxa upregulation and sensitization to BH3 mimetic ABT-737 in human Breast Cancer cells. Breast Cancer Res 2012;14(3):R96.
132. Al-Hussaini H, Subramanyam D, Reedijk M, et al. Notch signaling pathway as a therapeutic target in breast cancer. Mol Cancer Ther 2011;10:9-15.
133. Fitzgerald K, Harrington A, Leder P. Ras pathway signals are required for notch-mediated oncogenesis. Oncogene 2000;19:4191-8.
134. Liao WR, Hsieh RH, Hsu KW, et al. The CBF1-independent Notch1 signal pathway activates human c-myc expression partially via transcription factor YY1. Carcinogenesis 2007;28:1867-76.
135. Mungamuri SK, Yang X, Thor AD, et al. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res 2006;66:4715-24.
136. Weijzen S, Rizzo P, Braid M, et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nature Med 2002;8:979-86.
137. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007;35(4):495-516.
138. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-74.
139. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007;26:1324-37.
140. Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nature Rev Cancer 2002;2:420-30.
141. Takeda K, Stagg J, Yagita H, et al. Targeting death-inducing receptors in cancer therapy. Oncogene 2007;26:3745-57.
142. Abdulghani J, El-Deiry WS. TRAIL receptor signaling and therapeutics. Expert Opin Ther Targets 2010;14:1091-108.
143. Buchsbaum DJ, Zhou T, Grizzle WE, et al. Antitumor efficacy of TRA-8 anti-DR5 monoclonal antibody alone or in combination with chemotherapy and/or radiation therapy in a human breast cancer model. Clin Cancer Res 2003;9(10 Pt 1):3731-41.
144. Londono-Joshi AI, Oliver PG, Li Y, et al. Basal-like breast cancer stem cells are sensitive to anti-DR5 mediated cytotoxicity. Breast Cancer Res Treat 2012;133:437-45.
145. Oliver PG, LoBuglio AF, Zhou T, et al. Effect of anti-DR5 and chemotherapy on basal-like breast cancer. Breast Cancer Res Treat 2012;133:417-26.
146. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998;281:1322-6.
147. de Almagro MC, Vucic D. The inhibitor of apoptosis (IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy. Exp Oncol 2012;34:200-11.
148. Straub CS. Targeting IAPs as an approach to anti-cancer therapy. Curr Top Med Chem 2011;11:291-316.
149. Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nature Rev Cancer 2002;2:647-56.
150. Kelly PN, Strasser A. The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ 2011;18:1414-24.
151. Puthalakath H, Strasser A. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 2002;9:505-12.
152. Chen L, Willis SN, Wei A, et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 2005;17:393-403.
153. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 2009;15:1126-32.
154. Tsujimoto Y, Finger LR, Yunis J, et al. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 1984;226:1097-9.
155. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988;335:440-2.
156. Cella N, Groner B, Hynes NE. Characterization of Stat5a and Stat5b homodimers and heterodimers and their association with the glucocortiocoid receptor in mammary cells. Mol Cell Biol 1998;18:1783-92.
157. Dawson SJ, Makretsov N, Blows FM, et al. BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer 2010;27:27.
158. Bhargava V, Kell DL, van de Rijn M, et al. Bcl-2 immunoreactivity in breast carcinoma correlates with hormone receptor positivity. Am J Pathol 1994;145:535-40.
159. Hwang KT, Woo JW, Shin HC, et al. Prognostic influence of BCL2 expression in breast cancer. Int J Cancer 2012;131:E1109-19.
160. Kallel-Bayoudh I, Hassen HB, Khabir A, et al. Bcl-2 expression and triple negative profile in breast carcinoma. Med Oncol 2010;2:2.
161. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817-26.
162. Oakes SR, Vaillant F, Lim E, et al. Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737. Proc Natl Acad Sci 2012;109:2766-71.
163. Certo M, Del Gaizo Moore V, Nishino M, et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 2006;9:351-65.
164. Deng J, Carlson N, Takeyama K, et al. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 2007;12:171-85.
165. Chonghaile TN, Letai A. Mimicking the BH3 domain to kill cancer cells. Oncogene 2008;27(Suppl 1):S149-57.
166. Moulder SL, Symmans WF, Booser DJ, et al. Phase I/II study of G3139 (Bcl-2 antisense oligonucleotide) in combination with doxorubicin and docetaxel in breast cancer. Clinical Cancer Res 2008;14:7909-16.
167. Becattini B, Kitada S, Leone M, et al. Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X(L). Chem Biol 2004;11:389-95.
168. Kitada S, Leone M, Sareth S, et al. Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem 2003;46:4259-64.
169. Kisim A, Atmaca H, Cakar B, et al. Pretreatment with AT-101 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of breast cancer cells by inducing death receptors 4 and 5 protein levels. J Cancer Res Clin Oncol 2012;138:1155-63.
170. Gao P, Bauvy C, Souquere S, et al. The Bcl-2 homology domain 3 mimetic gossypol induces both Beclin 1-dependent and Beclin 1-independent cytoprotective autophagy in cancer cells. J Biol Chem 2010;285:25570-81.
171. Mitchell C, Yacoub A, Hossein H, et al. Inhibition of MCL-1 in breast cancer cells promotes cell death in vitro and in vivo. Cancer Biol Ther 2010;10:903-17.
172. Arisan ED, Kutuk O, Tezil T, et al. Small inhibitor of Bcl-2, HA14-1, selectively enhanced the apoptotic effect of cisplatin by modulating Bcl-2 family members in MDA-MB-231 breast cancer cells. Breast Cancer Res Treat 2010;119:271-81.
173. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435:677-81.
174. Mason KD, Khaw SL, Rayeroux KC, et al. The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia. Leukemia 2009;23:2034-41.
175. van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006;10:389-99.
176. Kutuk O, Letai A. Alteration of the mitochondrial apoptotic pathway is key to acquired paclitaxel resistance and can be reversed by ABT-737. Cancer Res 2008;68:7985-94.
177. Kutuk O, Letai A. Displacement of Bim by Bmf and Puma rather than increase in Bim level mediates paclitaxel-induced apoptosis in breast cancer cells. Cell Death Differ 2010;17:1624-35.
178. Lee EF, Czabotar PE, van Delft MF, et al. A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation. J Cell Biol 2008;180:341-55.
179. Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev 2012;26:120-5.
180. Cragg MS, Harris C, Strasser A, et al. Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics. Nature Rev Cancer 2009;9:321-6.
181. Schoenwaelder SM, Jarman KE, Gardiner EE, et al. Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets. Blood 2011;118:1663-74.
182. Strasser A, Cory S, Adams JM. Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases. EMBO J 2011;30:3667-83.