958
Views
39
CrossRef citations to date
0
Altmetric
Review

Triple-negative breast cancer: investigating potential molecular therapeutic target

, MD, , MD, , MD (Full Professor of Medical Oncology) , , MD PhD, , MD & , MD PhD

Bibliography

  • Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med 2010;363:1938-48
  • Dent R, Hanna WM, Trudeau M, et al. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 2009;115(2):423-8
  • Bonotto M, Gerratana L, Poletto E, et al. Measures of outcome in metastatic breast cancer: insights from a real-world scenario. Oncologist 2014;19:1-8
  • Hicks DG, Short SM, Prescott NL, et al. Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. Am J Surg Pathol 2006;30(9):1097-04
  • Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology 2008;52(1):108-18
  • Weigelt B, Baehner FL, Reis-Filho JS. The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade. J Pathol 2010;220:263-80
  • Ghasemi R, Grassadonia A, Tinari N, et al. Tumor-derived microvesicles: the metastasomes. Med Hypotheses 2013;80(1):75-82
  • 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(7):2750-67
  • Vici P, Pizzuti L, Gamucci T, et al. Non-pegylated liposomal Doxorubicin-cyclophosphamide in sequential regimens with taxanes as neoadjuvant chemotherapy in breast cancer patients. J Cancer 2014;5(6):398-405
  • Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science 2001;291:1304-51
  • Forbes SA, Bindal N, Bamford S, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 2011;39:D945-50
  • Garraway LA, Lander ES. Lessons from the cancer genome. Cell 2013;153:17-37
  • Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science 2013;339:1546-58
  • Govind AP, Thampan RV. Membrane associated estrogen receptors and related proteins: localization at the plasma membrane and the endoplasmic reticulum. Mol Cell Biochem 2003;253:233-40
  • Razandi M, Pedram A, Park ST, Levin ER. Proximal events in signaling by plasma membrane estrogen receptors. J Biol Chem 2003;278:2701-12
  • Toran-Allerand CD, Guan X, MacLusky NJ. ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J Neurosci 2002;22:8391-401
  • Prossnitz ER, Sklar LA, Oprea TI, Arterburn JB. GPR30: a novel therapeutic target in estrogen-related disease. Trends Pharmacol Sci 2008; 29:116-23
  • Chen GG, Zeng Q, Tse GM. Estrogen and its receptors in cancer. Med Res Rev 2008;28:954-74
  • Prossnitz ER, Arterburn JB, Sklar LA. GPR30: a G protein-coupled receptor for estrogen. Mol Cell Endocrinol 2007;265–266:138-42
  • Prossnitz ER, Oprea TI, Sklar LA, Arterburn JB. The ins and outs of GPR30: a transmembrane estrogen receptor. J Steroid Biochem Mol Biol 2008;109:350-3
  • Maggiolini M, Vivacqua A, Fasanella G, et al. The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells. J Biol Chem 2004;279:27008-16
  • Katzenellenbogen BS, Frasor J. Therapeutic targeting in the estrogen receptor hormonal pathway. Semin Oncol 2004;31:28-38
  • Fox EM, Davis RJ, Shupnik MA. ERbeta in breast cancer--onlooker, passive player, or active protector? Steroids 2008;73:1039-51
  • Williams C, Edvardsson K, Lewandowski SA, et al. A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells. Oncogene 2008;27:1019-32
  • Skliris GP, Leygue E, Curtis-Snell L, et al. Expression of oestrogen receptor beta in oestrogen receptor-alpha negative human breast tumours. Br J Cancer 2006;95:616-26
  • Skliris GP, Leygue E, Watson PH, Murphy LC. Estrogen receptor alpha negative breast cancer patients: estrogen receptor beta as a therapeutic target. J Steroid Biochem Mol Biol 2008;109:1-10
  • Mann S, Laucirica R, Carlson N, et al. Estrogen receptor beta expression in invasive breast cancer. Hum Pathol 2001;32:113-18
  • Gucalp A, Traina TA. Triple-negative breast cancer: role of the androgen receptor. Cancer J 2010;16:62-5
  • Park S, Koo J, Park HS, et al. Expression of androgen receptors in primary breast cancer. Ann Oncol 2010;21:488-92
  • Isola JJ. Immunohistochemical demonstration of androgen receptor in breast cancer and its relationship to other prognostic factors. J Pathol 1993;170:31-5
  • Poola I, Abraham J, Baldwin K, et al. Estrogen receptors beta4 and beta5 are full length functionally distinct ERbeta isoforms: cloning from human ovary and functional characterization. Endocrine 2005;27:227-38
  • Litwiniuk MM, Roznowski K, Filas V, et al. Expression of estrogen receptor beta in the breast carcinoma of BRCA1 mutation carriers. BMC Cancer 2008;8:100
  • Novelli F, Milella M, Melucci E, et al. A divergent role for estrogen receptor-beta in node-positive and node-negative breast cancer classified according to molecular subtypes: an observational prospective study. Breast Cancer Res 2008;10:R74
  • Mandusic V, Nikolic-Vukosavelic D, Tanic N, et al. Expression of estrogen receptor beta wt isoform (ERbeta1) and ERbetaDelta5 splice variant mRNAs in sporadic breast cancer. J Cancer Res Clin Oncol 2007;133:571-9
  • Shaaban AM, Green AR, Karthik S, et al. Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients. Clin Cancer Res 2008;14:5228-35
  • Treeck O, Lattrich C, Springwald A, Ortmann O. Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells. Breast Cancer Res Treat 2010;120:557-65
  • Filardo EJ, Quinn JA, Frackelton ARJr, Bland KI. Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Mol Endocrinol 2002;16:70-84
  • Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membrane receptor coupled to a G-protein in human breast cancer cells. Endocrinology 2005;146:624-32
  • Filardo EJ, Quinn JA, Bland KI, Frackelton ARJr. Estrogen-induced activation of Erk–1 and Erk–2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 2000;14:1649-60
  • Girgert R, Emons G, Gru¨ndker C. Inactivation of GPR30 reduces growth of triple-negative breast cancer cells: possible application in targeted therapy. Breast Cancer Res Treat 2005;134:199-205
  • Niemeier LA, Dabbs DJ, Beriwal S, et al. Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol 2010;23:205-12
  • Moinfar F, Okcu M, Tsybrovskyy O, et al. Androgen receptors frequently are expressed in breast carcinomas: potential relevance to new therapeutic strategies. Cancer 2003;98:703-11
  • ClinicalTrials.gov. Bicalutamide in treating patients with metastatic breast cancer. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00468715
  • Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-52
  • 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
  • Duffy MJ, McKiernan E, O’Donovan N, et al. Role of ADAMs in cancer formation and progression. Clin Cancer Res 2009;15:1140-4
  • Konecny G, Pauletti G, Pegram M, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 2003;95:142-53
  • Tan DS, Marchio C, Jones RL, et al. Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat 2008;111(1):27-44
  • Blobel CP. ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 2005;6:32-43
  • Sahin U, Weskamp G, Kelly K, et al. Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol 2004;164:769-79
  • Stern DF. ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer. J Mammary Gland Biol Neoplasia 2008;13:215-23
  • 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
  • Wajant H. The role of TNF in cancer. Results Probl Cell Differ 2009;49:1-15
  • Finn RS. Targeting Src in breast cancer. Ann Oncol 2008;19:1379-86
  • Tryfonopoulos D, Walsh S, Collins DM, et al. Src: a potential target for the treatment of triple-negative breast cancer. Ann oncol 2011;22(10):2234-40
  • Elsberger B, Tan BA, Mitchell TJ, et al. Is expression or activation of Src kinase associated with cancer-specific survival in ER-, PR- and HER2-negative breast cancer patients? Am J Pathol 2009;175:1389-97
  • Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem 1998;67:481-507
  • Gewinner C, Wang ZC, Richardson A, et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 2009;16:115-25
  • Li J. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943-7
  • Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 2005;102:802-7
  • Toker A. Achieving specificity in Akt signaling in cancer. Adv Biol Regul 2012;52:78-87
  • Banerji S, Cibulskis K, Rangel-Escareno C, et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 2012;486:405-9
  • Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648-57
  • Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70
  • Di Paola RS, Kuczynski WI, Onodera K, et al. Evidence for a functional kit receptor in melanoma, breast, and lung carcinoma cells. Cancer Gene Ther 1997;4:176-82
  • Tsutsui S, Yasuda K, Suzuki K, et al. A loss of c-kit expression is associated with an advanced stage and poor prognosis in breast cancer. Br J Cancer 2006;94:1874-8
  • Kashiwagi S, Yashiro M, Takashima T, et al. c-Kit expression as a prognostic molecular marker in patients with basal-like breast cancer. Br J Surg 2013;100(4):490-6
  • Resar LMS. The high mobility group A1 gene: transforming inflammatory signals into cancer? Cancer Res 2010;70:436-9
  • Fusco A, Fedele M. Roles of HMGA proteins in cancer. Nat Rev Cancer 2007;7:899-910
  • Ben-Porath I, Thomson MW, Carey VJ, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008;40:499-507
  • Reeves R, Edberg DD, Li Y. Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells. Mol Cell Biol 2001;21:575-94
  • Mani SA, Guo W, Liao MJ, et al. The epithelial mesenchymal transition generates cells with properties of stem cells. Cell 2008;133:704-15
  • Shah SN, Cope L, Poh W, et al. HMGA1: a master regulator of tumor progression in triple-negative breast cancer cells. PLoS One 2013;8(5):e63419
  • Marumoto T, Zhang D, Saya H. Aurora-A - a guardian of poles. Nat Rev Cancer 2005;5:42-50
  • Miyoshi Y, Iwao K, Egawa C, Noguchi S. Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers. Int J Cancer 2001;92:370-3
  • Nadler Y, Camp RL, Schwartz C, et al. Expression of Aurora A (but not Aurora B) is predictive of survival in breast cancer. Clin Cancer Res 2008;14:4455-62
  • Wang LH, Xiang J, Yan M, et al. The mitotic kinase Aurora-A induces mammary cell migration and breast cancer metastasis by activating the Cofilin-F-actin pathway. Cancer Res 2010;70:9118-28
  • Xu J, Wu X, Zhou W, et al. Aurora-A identifies early recurrence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer. PLoS One 2013;8(2):e56919
  • Eilers M, Eisenman RN. Myc’s broad reach. Genes Dev 2008;22:2755-66
  • Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nat Rev Cancer 2008;8:976-90
  • Alles MC, Gardiner-Garden M, Nott DJ, et al. Meta-analysis and gene set enrichment relative to ER status reveal elevated activity of MYC and E2F in the “basal” breast cancer subgroup. PLoS One 2009;4:e4710
  • Cowling VH, Cole MD. mechanism of transcriptional activation by the Myc oncoproteins. Semin Cancer Biol 2006;16:242-52
  • Reinhardt HC, Jiang H, Hemann MT, Yaffe MB. Exploiting synthetic lethal interactions for targeted cancer therapy. Cell Cycle 2009;8:3112-19
  • Cermelli S, Jang IS, Bernard B, Grandori C. “Synthetic lethal screens as a means to understand and treat MYC-driven cancers”. Cold Spring Harb Perspect Med 2014;4:3
  • Finn OJ, Jerome KR, Henderson RA, et al. MUC1 epithelial tumor mucin-based immunity and cancer vaccines. Immunol Rev 1995;145:61-89
  • Karanikas V, Hwang LA, Pearson J, et al. Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-MUC1 fusion protein. J Clin Invest 1997;100:2783-92
  • Rahn JJ, Dabbagh L, Pasdar M, Hugh JC. The importance of MUC1 cellular localization in patients with breast carcinoma: an immunohistologic study of 71 patients and review of the literature. Cancer 2001;91:1973-82
  • Ciborowski P, Finn OJ. Non-glycosylated tandem repeats of MUC1 facilitate attachment of breast tumor cells to normal human lung tissue and immobilized extracellular matrix proteins (ECM) in vitro: potential role in metastasis. Clin Exp Metastasis 2002;19:339-45
  • van der Vegt B, de Roos MA, Peterse JL, et al. The expression pattern of MUC1 (EMA) is related to tumour characteristics and clinical outcome of invasive ductal breast carcinoma. J Histopathol 2007;51:322-35
  • Bitler BG, Goverdhan A, Schroeder JA. MUC1 regulates nuclear localization and function of the epidermal growth factor receptor. J Cell Sci 2010;123:1716-23
  • Pochampalli MR, el Bejjani RM, Schroeder JA. MUC1 is a novel regulator of ErbB1 receptor trafficking. Oncogene 2007;26:1693-701
  • Hanna JA, Bordeaux J, Rimm DL, Agarwal S. The function, proteolytic processing, and histopathology of Met in cancer. Adv Cancer Res 2009;103:1-23
  • Gastaldi S, Comoglio PM, Trusolino L. The Met oncogene and basal-like breast cancer: another culprit to watch out for? Breast Cancer Res 2010;12:208
  • Peschard P, Park M. From Tpr-Met to Met, tumorigenesis and tubes. Oncogene 2007;26:1276-85
  • Lengyel E, Prechtel D, Resau JH, et al. C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer 2005;113:678-82
  • Tolgay Ocal I, Dolled-Filhart M, D’Aquila TG, et al. Tissue microarray-based studies of patients with lymph node negative breast carcinoma show that met expression is associated with worse outcome but is not correlated with epidermal growth factor family receptors. Cancer 2003;97:1841-8
  • Charafe-Jauffret E, Ginestier C, Monville F, et al. Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 2006;25:2273-84
  • Garcia S, Dale`s JP, Charafe-Jauffret E, et al. Poor prognosis in breast carcinomas correlates with increased expression of targetable CD146 and c-Met and with proteomic basal-like phenotype. Hum Pathol 2007;38:830-41
  • Kim YJ, Choi JS, Seo J, et al. MET is a potential target for use in combination therapy with EGFR inhibition in triple-negative/basal-like breast cancer. Int J Cancer 2014;134(10):2424-36
  • Bos JL. The ras gene family and human carcinogenesis. Mutat Res 1988;195:255-71
  • Zarbl H, Sukumar S, Arthur AV, et al. Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats. Nature 1985;315:382-5
  • Balmain A, Pragnell IB. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature 1983;303:72-4
  • Sukumar S. Ras oncogenes in chemical carcinogenesis. Curr Top. Microbiol Immunol 1989;148:93-114
  • De Biasi F, Del Sal G, Hand PH. Evidence of enhancement of the ras oncogene protein product (p21) in a spectrum of human tumors. Int J Cancer 1989;43:431-5
  • Thor A, Ohuchi N, Hand PH, et al. Ras gene alterations and enhanced levels of ras p21 expression in a spectrum of benign and malignant human mammary tissues. Lab Invest 1986;55:603-15
  • Spandidos DA, Agnantis NJ. Human malignant tumours of the breast, as compared to their respective normal tissue, have elevated expression of the Harvey ras oncogene. Anticancer Res 1984;4:269-72
  • Reddy EP, Reynolds RK, Santos E, Barbacid M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 1982;300:149-52
  • Tabin CJ, Bradely SM, Bargmann CI, et al. Mechanism of activation of a human oncogene. Nature 1982;300:143-9
  • Taparowsky E, Shimizu K, Goldfarb M, Wigler M. Structure and activation of the human N-ras gene. Cell 1983;34:581-6
  • Chang EH, Furth ME, Scolnick EM, Lowry DR. Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus. Nature 1982;297:479-83
  • Westaway D, Paplioff J, Moscorini C, Varmus C. Identification of a provirally activated c-Ha-ras oncogene in an avian nephroblastoma via a novel procedure: cDNA cloning of a chimaeric viral-host transcript. EMBO J 1986;5:301-6
  • Sklar MD. Increased resistance to cis-diamminedichloroplatinum(II) in NIH 3T3 cells transformed by ras oncogenes. Cancer Res 1988;48:793-7
  • Gupta AK, Bakanauskas VJ, Cerniglia GJ, et al. The ras radiation resistance pathway. Cancer Res 2001;61:4278-82
  • Jones HA, Hahn SM, Bernhard E, McKenna WG. Ras inhibitors and radiation therapy. Semin Radiat Oncol 2001;11:328-37
  • Ali IU, Lidereau R, Theillet C, Callahan R. Reduction to homozygosity of genes on chromosome 11 in human breast neoplasia. Science (Wash. DC) 1987;238:185-8
  • Theillet C, Liderau R, Escot C, et al. Loss of a c-H-ras-1 allele and aggressive human primary breast carcinomas. Cancer Res 1986;46:4776-81
  • Kasid A, Lippman ME, Papageorge AG, et al. Transfection of v-rasH DNA into MCF-7 human breast cancer cells bypasses dependence on estrogen for tumorigenicity. Science 1985;228:725-8
  • Kraus MH, Yuasa Y, Aarinson SA. A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient. Proc Natl Acad Sci USA 1984;81:5384-8
  • Bos JL. Ras oncogenes in human cancer: a review. Cancer Res 1989;49:4682-9
  • Craig DW, O’Shaughnessy JA, Kiefer JA, et al. Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities. Mol Cancer Ther 2013;12:104-116
  • Lodish H, Berk A, Zipursky SL, et al. Molecular cell biology. 4th edition. W. H. Freeman; New York: 2000; Section 24.2, Proto-Oncogenes and Tumor-Suppressor Genes
  • Evans DG, Howell A, Ward D, et al. Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer. J Med Genet 2011;48(8):520-2
  • Meyer P, Landgraf K, Högel B, et al. BRCA2 mutations and triple-negative breast cancer. PLoS One 2012;5):e38361
  • Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008;26:4282-8
  • Richardson AL, Wang ZC, De Nicolo A, et al. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 2006;69:121-32
  • Collavin L, Lunardi A, Del Sal G. P53-family proteins and their regulators:hubs and spokes intumor suppression. Cell Death Differ 2010;17:901-11
  • Luciani MG, Hutchins JR, Zheleva D, et al. The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A. J Mol Biol 2000;300:503-18
  • Di Agostino S, Strano S, Emiliozzi V, et al. Gain of function of mutant p53:the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell 2006;10:191-202
  • Adorno M, Cordenonsi M, Montagner M, et al. A mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell 2009;137:87-98
  • Goldstein I, Marcel V, Olivier M, et al. Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies. Cancer Gene Ther 2011;18:2-11
  • Bisso A, Collavin L, Del Sal G. P73 as a pharmaceutical target for cancer therapy. Curr Pharm Des 2011;17:578-90
  • Du Z, Li J, Wang L, et al. Overexpression of Delta Np63 alpha induces a stem cell phenotype in MCF7 breast carcinoma cell line through the Notch pathway. Cancer Sci 2010;101:2417-24
  • Leong CO, Vidnovic N, DeYoung MP, et al. The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J Clin Invest 2007;117:1370-80
  • 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
  • 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 2008;10:R101
  • Umemura S, Yoshida S, Ohta Y, et al. Increased phosphorylation of Akt in triple-negative breast cancers. Cancer Sci 2007;98:1889-92
  • Iqbal J, Thike AA, Cheok PY, et al. Insulin growth factor receptor-1 expression and loss of PTEN protein predict early recurrence in triple-negative breast cancer. Histopathology 2012;61:652-9
  • Badve S, Collins NR, Bhat-Nakshatri P, et al. Subcellular localization of activated AKT in estrogen receptor- and progesterone receptor-expressing breast cancers: potential clinical implications. Am J Pathol 2010;176:2139-49
  • Tsai E-M, Wang S-C, Lee J-N, Mien-Hung M-C. Akt Activation by estrogen in estrogen receptor-negative breast cancer cells. Cancer Res 2001;61:8390-2
  • Burkhart D, Sage J. Cellular mechanisms of tumor suppression by the retinoblastoma gene. Nat Rev 2008;8:1-12
  • Sherr CJ. Cancer cell cycles. Science 1996;274:1672-7
  • Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res 2008;10:75
  • Neve RM, Chin K, Fridlyand J, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 2006;10:515-27
  • Jiang Z, Jones R, Liu JC, et al. RB1 and p53 at the crossroad of EMT and triple-negative breast cancer. Cell Cycle 2011;10:1563-70
  • Robinson TJW, Liu JC, Vizeacoumar F, et al. RB1 status in triple negative breast cancer cells dictates response to radiation treatment and selective therapeutic drugs. PLoS One 2013;8(11):e78641
  • Trere D, Brighenti E, Donati G, et al. High prevalence of retinoblastoma protein loss in triple-negative breast cancers and its association with a good prognosis in patients treated with adjuvant chemotherapy. Ann Oncol 2009;20:1818-23
  • Schreiber V, Dantzer F, Ame JC, de Murcia G. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 2006;7:517-28
  • Hassa PO, Hottiger MO. The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front Biosci 2008;13:3046-82
  • Schreiber V, Ame JC, Dolle P, et al. Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 2002;277:23028-36
  • Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double strand break repair. J Clin Oncol 2008;26:3785-90
  • Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434:913-17
  • Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-21
  • De Soto JA, Deng CX. PARP-1 inhibitors: are they the long-sought genetically specific drugs for BRCA1/2-associated breast cancers? Int J Med Sci 2006;3:117-23
  • Come C, Laine A, Chanrion M, et al. CIP2A is associated with human breast cancer aggressivity. Clin Cancer Res 2009;15:5092-100
  • Chen KF, Liu CY, Lin YC, et al. CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene 2010;29:6257-66
  • Niemela M, Kauko O, Sihto H, et al. CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. Oncogene 2012;31(39):4266-78
  • Kang S, Dong S, Gu TL, et al. FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway. Cancer Cell 2007;12:201-14
  • Law JH, Habibi G, Hu K, et al. Phosphorylated insulin-like growth factor-1/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 2008;68:10238-46
  • Anjum R, Blenis J. The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol 2008;9:747-58
  • Chen R-H, Abate C, Blenis J. Phosphorylation of the c-Fos transrepression domain by mitogen-activated protein kinase and 90-kDa ribosomal S6 kinase. Proc Natl Acad Sci USA 1993;90:10952-6
  • Shimamura A, Ballif BA, Richards SA, et al. Rsk1 mediates a MEKMAP kinase cell survival signal. Curr Biol 2000;10:127-35
  • Sassone-Corsi P, Mizzen CA, Cheung P, et al. Requirement of RSK2 for epidermal growth factor-activated phosphorylation of histone H3. Science 1999;285:886-91
  • Davies AH, Barrett I, Pambid MR, et al. YB-1 evokes susceptibility to cancer through cytokinesis failure, mitotic dysfunction and HER2 amplification. Oncogene 2011;30:3649-60
  • Habibi G, Leung S, Law JH, et al. Re-defining prognostic factors for breast cancer: YB-1 is a stronger predictor of relapse and disease specific survival than estrogen receptor or HER-2 across all tumor subtypes. Breast Cancer Res 2008;10:R86
  • Reipas KM, Law JH, Couto N, et al. Luteolin is a novel p90 ribosomal S6 kinase (RSK) inhibitor that suppresses Notch4 signaling by blocking the activation of Y-box binding protein-1 (YB-1). Oncotarget 2013;4(2):329-45
  • Charafe-Jauffret E, Ginestier C, Iovino F, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 2009;69:1302-13
  • Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008;100:672-9
  • Stratford AL, Reipas K, Maxwell C, et al. Targeting tumour-initiating cells to improve the cure rates for triple-negative breast cancer. Expert Rev Mol Med 2010;12:e22
  • Stratford AL, Reipas K, Hu K. Targeting p90 ribosomal S6 kinase eliminates tumor-initiating cells by inactivating Y-box binding protein-1 in triple-negative breast cancers. Stem Cells 2012;30:1338-48
  • Jones MH, Huneycutt BJ, Pearson CG, et al. Chemical genetics reveals a role for Mps1 kinase in kinetochore attachment during mitosis. Curr Biol 2005;15:160-5
  • Yuan B, Xu Y, Woo JH, et al. Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability. Clin Cancer Res 2006;12:405-10
  • Janssen A, Kops GJ, Medema RH. Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells. Proc Natl Acad Sci USA 2009;106:19108-13
  • Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 2005;5:773-85
  • Daniel J, Coulter J, Woo JH, et al. High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells. Proc Natl Acad Sci USA 2011;108:5384-9
  • Rogakou EP, Nieves-Neira W, Boon C, et al. Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139. J Biol Chem 2000;275:9390-5
  • Janssen A, van der Burg M, Szuhai K, et al. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 2011;333:1895-8
  • Wei JH, Chou YF, Ou YH, et al. TTK/hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68. J Biol Chem 2005;280:7748-57
  • Leng M, Chan DW, Luo H, et al. MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability. Proc Natl Acad Sci USA 2006;103:11485-90
  • Turner N, Tutt A, Ashworth A. Hallmarks of ’BRCAness’ in sporadic cancers. Nat Rev Cancer 2004;4:814-19
  • Brough R, Frankum JR, Sims D, et al. Functional viability profiles of breast cancer. Cancer Discov 2011;1:260-73
  • Kilpinen S, Ojala K, Kallioniemi O. Analysis of kinase gene expression patterns across 5681 human tissue samples reveals functional genomic taxonomy of the kinome. PLoS One 2010;5:e15068
  • Hadad SM, Fleming S, Thompson AM. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Crit Rev Oncol Hematol 2008;67:1-7
  • Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 2009;9:563-75
  • Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007;8:774-85
  • Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577-90
  • Jones RG, Plas DR, Kubek S, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 2005;18:283-93
  • Leprivier G, Remke M, Rotblat B, et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 2013;153:1064-79
  • Shaw RJ, Bardeesy N, Manning BD. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004;6:91-9
  • Guo D, Hildebrandt IJ, Prins RM, et al. The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. Proc Natl Acad Sci USA 2009;106:12932-7
  • Dunwoodie SL, Henrique D, Harrison SM, Beddington RS. Mouse DII3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development 1997;124:3065-76
  • Lindsell CE, Shawber CJ, Boulter J, Weinmaster G. Jagged: a mammalian ligand that activates Notch1. Cell 1995;80:909-17
  • Callahan R, Raafat A. A Notch signaling in mammary gland tumorigenesis. J Mammary Gland Biol Neoplasia 2001;6:23-6
  • Wang J, Fu L, Gu F, Ma Y. Notch1 is involved in migration and invasion of human breast cancer cells. Oncol Report 2011;26:1295-303
  • Harrison H, Farnie G, Howell SJ, et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 2010;70:709-18
  • Pear WS, Aster JC, Scott ML, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 1996;183:2283-91
  • Nicolas M, Wolfer A, Raj K, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 2003;416-21
  • Nagamatsu I, Onishi H, Matsushita S. NOTCH4 is a potential therapeutic target for triple-negative breast cancer. Anticancer Res 2014;34:69-80
  • Chen J, Imanaka N, Chen J, Griffin JD. Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br J Cancer 2009;102:351-60
  • Fish JE, Santoro MM, Morton SU, et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 2008;15:272-84
  • Cho WC. OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer 2007;6:60
  • Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006;6:857-66
  • Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215-33
  • Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature 2005;435:834-8
  • Drakaki A, Iliopoulos D. MicroRNA Gene networks in oncogenesis. Curr Genomics 2009;10:35-41
  • Negrini M, Calin GA. Breast cancer metastasis: a microRNA story. Breast Cancer Res 2008;10:203
  • Stenvang J, Silahtaroglu AN, Lindow M, et al. The utility of LNA in microRNA-based cancer diagnostics and therapeutics. Semin Cancer Biol 2008;18:89-102
  • Zhang W, Dahlberg JE, Tam W. MicroRNAs in tumorigenesis: a primer. Am J Pathol 2007;171:728-38
  • Bao B, Ali S, Kong D, et al. Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer. PLoS One 2011;6:e17850
  • Heyn H, Engelmann M, Schreek S, et al. MicroRNA miR-335 is crucial for the BRCA1 regulatory cascade in breast cancer development. Int J Cancer 2011;129:2797-06
  • He L, He X, Lim LP, et al. A microRNA component of the p53 tumour suppressor network. Nature 2007;447:1130-4
  • Schetter AJ, Leung SY, Sohn JJ, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 2008;299:425-36
  • Boll K, Reiche K, Kasack K, et al. MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma. Oncogene 2013;32:277-85
  • Wang C, Zheng X, Shen C, Shi Y. MicroRNA-203 suppresses cell proliferation and migration by targeting BIRC5 and LASP1 in human triple-negative breast cancer cells. J Exp Clin Cancer Res 2012;31:58
  • Foekens JA, Sieuwerts AM, Smid M, et al. Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer. Proc Natl Acad Sci USA 2008;105:13021-6
  • Toyama T, Yamashita H, Kondo N, et al. Frequently increased epidermal growth factor receptor (EGFR) copy numbers and decreased BRCA1 mRNA expression in Japanese triple-negative breast cancers. BMC Cancer 2008;8:309
  • Toyama T, Kondo N, Endo Y, et al. High expression of microRNA-210 is an independent factor indicating a poor prognosis in japanese triple-negative breast cancer patients. Jpn J Clin Oncol 2012;42:256-63
  • Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967-74
  • Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:1011-27
  • Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 2003;9:677-84
  • Koch S, Tugues S, Li X, et al. Signal transduction by vascular endothelial growth factor receptors. Biochem J 2011;437:169-83
  • Nasarre P, Kusy S, Constantin B, et al. Semaphorin SEMA3F has a repulsing activity on breast cancer cells and inhibits E-cadherin mediated cell adhesion. Neoplasia 2005;7:180-9
  • Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M. Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res 2006;312:584-93
  • Kigel B, Varshavsky A, Kessler O, Neufeld G. Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells. PLoS One 2008;3:e3287
  • Ryden L, Jirstrom K, Haglund M, et al. Epidermal growth factor receptor and vascular endothelial growth factor receptor 2 are specific biomarkers in triple-negative breast cancer. Results from a controlled randomized trial with long-term follow-up. Breast Cancer Res Treat 2010;120:491-8
  • Staton CA, Shaw LA, Valluru et al. Expression of class 3 semaphorins and their receptors in human breast neoplasia. Histopathology 2011;59:274-82
  • Gabrovska PN, Smith RA, Tiang T, et al. Semaphorin-plexin signalling genes associated with human breast tumourigenesis. Gene 2011;489:63-9
  • Banu N, Teichman J, Dunlap-Brown M, et al. Semaphorin 3C regulates endothelial cell function by increasing integrin activity. FASEB J 2006;20:2150-2
  • Rossari JR, Metzger-Filho O, Paesmans M, et al. Bevacizumab and breast cancer: a meta-analysis of first-line phase III studies and a critical reappraisal of available evidence. J Oncol 2012;2012:417673
  • Mohammadi M, Olsen SK, Ibrahimi OA. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 2005;16:107-37
  • Furdui CM, Lew ED, Schlessinger J, Anderson KS. Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell 2006;21:711-17
  • Turner N, Lambros MB, Horlings HM, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene 2010;29:2013-23
  • Riese DJ, Stern DF. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays 1998;20:41-8
  • Miyamoto S, Yagi H, Yotsumoto F, et al. Heparin-binding epidermal growth factor-like growth factor as a novel targeting molecule for cancer therapy. Cancer Sci 2006;97:341-7
  • Mullenbrock S, Shah J, Cooper GM. Global expression analysis identified a preferentially nerve growth factor-induced transcriptional program regulated by sustained mitogen-activated protein kinase/extracellular signal–regulated kinase (ERK) and AP-1 protein activation during PC12 cell differentiation. J Biol Chem 2011;286:45131-45
  • Yotsumoto F, Oki E, Tokunaga E, et al. HB-EGF orchestrates the complex signals involved in triple-negative and trastuzumab-resistant breast cancer. Int J Cancer 2010;127:2707-17
  • Wang F, Liu R, Lee SW, et al. Heparin-binding EGF-like growth factor is an early response gene to chemotherapy and contributes to chemotherapy resistance. Oncogene 2007;26:2006-16
  • Ongusaha PP, Kwak JC, Zwible AJ, et al. HB-EGF is a potent inducer of tumor growth and angiogenesis. Cancer Res 2004;64:5283-90
  • Murata T, Mizushima H, Chinen I, et al. HB-EGF and PDGF mediate reciprocal interactions of carcinoma cells with cancer-associated fibroblasts to support progression of uterine cervical cancers. Cancer Res 2011;71:6633-42
  • Nakai K, Yoneda K, Moriue T, et al. HB-EGF induced VEGF production and eNOS activation depend on both PI3 kinase and MAP kinase in HaCaT cells. J Dermatol Sci 2009;55:170-8
  • Tan MJ, Teo Z, Sng MK, et al. Emerging roles of angiopoietin- like 4 in human cancer. Mol Cancer Res 2012;10:677-88
  • O’Shaughnessy J, Romieu G, Diéras V, et al. Meta-analysis of patients with triplenegative breast cancer (TNBC) from three randomized trials of first-line bevacizumab (BV) and chemotherapy treatment for metastatic breast cancer (MBC). Cancer Res 2010;70:abstract P6-12-03; presented data—SABCS 2010
  • Bramati A, Girelli S, Torri V, et al. Efficacy of biological agents in metastatic triple-negative breast cancer. Cancer Treat Rev 2014;40(5):605-13
  • Gerber B, Loibl S, Eidtmann H, et al. Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44). Ann Oncol 2013;24:2978-84
  • Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 2012;366(4):310-20
  • Cameron D, Brown J, Dent R, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 2013;14:933-42
  • Slamon DL, Swain SM, Buyse M, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive, or high-risk node-negative breast cancer [abstract S1-03]. 2013 San Antonio Breast Cancer Symposium; 2013
  • Untch M, Gerber B, Harbeck N, et al. 13th st. Gallen international breast cancer conference 2013: primary therapy of early breast cancer evidence, controversies, consensus - opinion of a german team of experts (zurich 2013). Breast Care (Basel) 2013;8(3):221-9
  • Tomao S, Romiti A, Tomao F, et al. A phase II trial of a biweekly combination of paclitaxel and gemcitabine in metastatic breast cancer. BMC Cancer 2006;6:137

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.