Triple Negative Breast Cancer: Molecular Classification, Prognostic Markers and Targeted Therapies


1 Department of Research and Education, Razavi Hospital, Mashhad, IR Iran

2 Student Research Committee, Mashhad University of Medical Sciences, Mashhad, IR Iran



Context: Triple negative breast cancer (TNBC) is a heterogeneous group of diseases that is negative for esterogen receptor (ER) progesteron receptor (PR) and human epidermal growth factor receptor 2 (HER2). This type of breast cancer is typically high-grade carcinomas, although low-grade tumors occur. The aim of this review is to focus on molecular classification and features, prognostic markers and targeted therapies of triple negative breast cancer. Evidence Acquisition: We searched using electronic databases Pubmed/Medline, Dare, Scopus, Embase, and Cochrane Database of Systematic Reviews with terms of ‘Triple negative breast cancer’, ‘Breast cancer’, ‘Molecular classification’, ‘Immunohistochemical markers’, ‘Molecular features, ‘Targeted therapy’, and ‘Prognostic marker’. Results: It seems that TNBC itself can be subdivided into immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor, and distinct basal-like subtypes that differ substantially from basal-like tumors. There are several prognostic makers for TNBC including EGFR and ALDH1, Lysyl Oxidase-Like 2 protein (LOXL2), Synuclein gamma (SNCG), LDHB (Lactate Dehydrogenase B). The antiangiogenic agents, EGFR inhibitors, and PARP inhibitors are new therapeutic Implications and potent factors to targeted therapies of TNBC. Conclusions: Only a few clinical trials are performed on TNBC patients because this disease has a low incidence. Therefore, it seems larger scale clinical trials are needed to be conducted in the future.


  1. 1.Redig AJ, McAllister SS. Breast cancer as a systemic disease: a view of metastasis. J Intern Med. 2013;274(2):113–26.

    1. Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12(4):207. 3. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295(21):2492–502.
    2. Oakman C, Viale G, Di Leo A. Management of triple negative breast cancer. Breast. 2010;19(5):312–21.
    3. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429–34.
    4. Perou CM. Molecular stratification of triple-negative breast cancers. Oncologist. 2010;15 Suppl 5:39–48.
    5. Dawood S. Triple-negative breast cancer: epidemiology and management options. Drugs. 2010;70(17):2247–58.
    6. Lara-Medina F, Perez-Sanchez V, Saavedra-Perez D, Blake-Cerda M, Arce C, Motola-Kuba D, et al. Triple-negative breast cancer in Hispanic patients: high prevalence, poor prognosis, and association with menopausal status, body mass index, and parity. Cancer. 2011;117(16):3658–69.
    7. Brady-West DC, McGrowder DA. Triple negative breast cancer: therapeutic and prognostic implications. Asian Pac J Cancer Prev. 2011;12(8):2139–43.
    8. Dolle JM, Daling JR, White E, Brinton LA, Doody DR, Porter PL, et al. Risk factors for triple-negative breast cancer in women under the age of 45 years. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1157–66.
    9. Bosch A, Eroles P, Zaragoza R, Vina JR, Lluch A. Triple-negative breast cancer: molecular features, pathogenesis, treatment and current lines of research. Cancer Treat Rev. 2010;36(3):206–15.
    10. Carey L, Winer E, Viale G, Cameron D, Gianni L. Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol. 2010;7(12):683–92.
    11. Rodriguez-Pinilla SM, Sarrio D, Honrado E, Hardisson D, Calero F, Benitez J, et al. Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res. 2006;12(5):1533–9.
    12. Foulkes WD, Stefansson IM, Chappuis PO, Begin LR, Goffin JR, Wong N, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst. 2003;95(19):1482–5. 15. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010;12(5):R68.
    13. Turner N, Lambros MB, Horlings HM, Pearson A, Sharpe R, Natrajan R, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene. 2010;29(14):2013–23.
    14. Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, et al. Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res. 2009;15(2):441–51.
    15. Rody A, Karn T, Liedtke C, Pusztai L, Ruckhaeberle E, Hanker L, et al. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res. 2011;13(5):R97.
    16. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, 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.
    17. Linn SC, Van 't Veer LJ. Clinical relevance of the triple-negative breast cancer concept: genetic basis and clinical utility of the concept. Eur J Cancer. 2009;45 Suppl 1:11–26.
    18. Turner N, Moretti E, Siclari O, Migliaccio I, Santarpia L, D'Incalci M, et al. Targeting triple negative breast cancer: is p53 the answer? Cancer Treat Rev. 2013;39(5):541–50.
    19. Purrington KS, Slager S, Eccles D, Yannoukakos D, Fasching PA, Miron P, et al. Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triplenegative breast cancer. Carcinogenesis. 2014;35(5):1012–9.
    20. Radojicic J, Zaravinos A, Vrekoussis T, Kafousi M, Spandidos DA, Stathopoulos EN. MicroRNA expression analysis in triple-negative (ER, PR and Her2/neu) breast cancer. Cell Cycle. 2011;10(3):507–17.
    21. de Rinaldis E, Gazinska P, Mera A, Modrusan Z, Fedorowicz GM, Burford B, et al. Integrated genomic analysis of triple-negative breast cancers reveals novel microRNAs associated with clinical and molecular phenotypes and sheds light on the pathways they control. BMC Genomics. 2013;14:643.
    22. Chen JQ , Russo J. ERalpha-negative and triple negative breast cancer: molecular features and potential therapeutic approaches. Biochim Biophys Acta. 2009;1796(2):162–75.
    23. Lowery AJ, Miller N, Devaney A, McNeill RE, Davoren PA, Lemetre C, et al. MicroRNA signatures predict oestrogen receptor, progesterone receptor and HER2/neu receptor status in breast cancer. Breast Cancer Res. 2009;11(3):R27.
    24. Bernardi R, Gianni L. Hallmarks of triple negative breast cancer emerging at last? Cell Res. 2014;24(8):904–5.
    25. Chen X, Iliopoulos D, Zhang Q , Tang Q, Greenblatt MB, Hatziapostolou M, et al. XBP1 promotes triple-negative breast cancer by controlling the HIF1alpha pathway. Nature. 2014;508(7494):103–7. 29. Criscitiello C, Sotiriou C, Ignatiadis M. Circulating tumor cells and emerging blood biomarkers in breast cancer. Curr Opin Oncol. 2010;22(6):552–8.
    26. Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Newell J, Kerin MJ. Circulating microRNAs as novel minimally invasive biomarkers for breast cancer. Ann Surg. 2010;251(3):499–505.
    27. Shiu KK, Tan DS, Reis-Filho JS. Development of therapeutic approaches to 'triple negative' phenotype breast cancer. Expert Opin Ther Targets. 2008;12(9):1123–37.
    28. Jackson B, Brocker C, Thompson DC, Black W, Vasiliou K, Nebert DW, et al. Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics. 2011;5(4):283–303.
    29. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555–67.
    30. Ohi Y, Umekita Y, Yoshioka T, Souda M, Rai Y, Sagara Y, et al. Aldehyde dehydrogenase 1 expression predicts poor prognosis in triple-negative breast cancer. Histopathology. 2011;59(4):776–80.
    31. Csiszar K. Lysyl oxidases: a novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol. 2001;70:1–32.
    32. Jiao Q , Wu A, Shao G, Peng H, Wang M, Ji S, et al. The latest progress in research on triple negative breast cancer (TNBC): risk factors, possible therapeutic targets and prognostic markers. J Thorac Dis. 2014;6(9):1329–35.
    33. Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N. Triple-negative breast cancer--current status and future directions. Ann Oncol. 2009;20(12):1913–27.
    34. Wu K, Huang S, Zhu M, Lu Y, Chen J, Wang Y, et al. Expression of synuclein gamma indicates poor prognosis of triple-negative breast cancer. Med Oncol. 2013;30(3):612.
    35. McCleland ML, Adler AS, Shang Y, Hunsaker T, Truong T, Peterson D, et al. An integrated genomic screen identifies LDHB as an essential gene for triple-negative breast cancer. Cancer Res. 2012;72(22):5812–23.
    36. Dennison JB, Molina JR, Mitra S, Gonzalez-Angulo AM, Balko JM, Kuba MG, et al. Lactate dehydrogenase B: a metabolic marker of response to neoadjuvant chemotherapy in breast cancer. Clin Cancer Res. 2013;19(13):3703–13.
    37. Singh-Ranger G, Salhab M, Mokbel K. The role of cyclooxygenase-2 in breast cancer: review. Breast Cancer Res Treat. 2008;109(2):189–98.
    38. Hoellen F, Kelling K, Dittmer C, Diedrich K, Friedrich M, Thill M. Impact of cyclooxygenase-2 in breast cancer. Anticancer Res. 2011;31(12):4359–67.
    39. Mosalpuria K, Hall C, Krishnamurthy S, Lodhi A, Hallman DM, Baraniuk MS, et al. Cyclooxygenase-2 expression in non-metastatic triple-negative breast cancer patients. Mol Clin Oncol. 2014;2(5):845–50.
    40. Urruticoechea A, Smith IE, Dowsett M. Proliferation marker Ki-67 in early breast cancer. J Clin Oncol. 2005;23(28):7212–20.
    41. Petit T, Wilt M, Velten M, Millon R, Rodier JF, Borel C, et al. Com- Jafarzadeh N et al. Razavi Int J Med. 2015;3(2):e24992 7 parative value of tumour grade, hormonal receptors, Ki-67, HER2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracyclinebased chemotherapy. Euro J of Cancer. 2004;40(2):205–11.
    42. Rhee J, Han SW, Oh DY, Kim JH, Im SA, Han W, et al. The clinicopathologic characteristics and prognostic significance of triplenegativity in node-negative breast cancer. BMC Cancer. 2008;8:307. 47. Keam B, Im SA, Lee KH, Han SW, Oh DY, Kim JH, et al. Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis. Breast Cancer Res. 2011;13(2):R22.
    43. Siziopikou KP, Ariga R, Proussaloglou KE, Gattuso P, Cobleigh M. The challenging estrogen receptor-negative/ progesterone receptor-negative/HER-2-negative patient: a promising candidate for epidermal growth factor receptor-targeted therapy? Breast J. 2006;12(4):360–2.
    44. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329–34.
    45. Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26(15):2568–81.
    46. Populo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci. 2012;13(2):1886–918.
    47. Burgess DJ, Doles J, Zender L, Xue W, Ma B, McCombie WR, et al. Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proc Natl Acad Sci U S A. 2008;105(26):9053–8.
    48. Sharpe R, Pearson A, Herrera-Abreu MT, Johnson D, Mackay A, Welti JC, et al. FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo. Clin Cancer Res. 2011;17(16):5275–86.
    49. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34.
    50. O’shaughnessy J, Osborne C, Pippen J, Yoffe M, Patt D, Monaghan G, et al., editors. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/ carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial.; ASCO Annual Meeting Proceedings.; 2009; p. 3.
    51. Chiosis G, Caldas Lopes E, Solit D. Heat shock protein-90 inhibitors: a chronicle from geldanamycin to today's agents. Curr Opin Investig Drugs. 2006;7(6):534–41.
    52. Patel HJ, Modi S, Chiosis G, Taldone T. Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment. Expert Opin Drug Discov. 2011;6(5):559–87.
    53. Kim LC, Song L, Haura EB. Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol. 2009;6(10):587–95.
    54. Finn RS, Bengala C, Ibrahim N, Roche H, Sparano J, Strauss LC, et al. Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res. 2011;17(21):6905–13.
    55. Tryfonopoulos D, Walsh S, Collins DM, Flanagan L, Quinn C, Corkery B, et al. Src: a potential target for the treatment of triple-negative breast cancer. Ann Oncol. 2011;22(10):2234–40.
    56. Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: expression in estrogen receptorpositive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol. 2010;23(2):205–12.
    57. Shah PD, Gucalp A, Traina TA. The role of the androgen receptor in triple-negative breast cancer. Womens Health (Lond Engl). 2013;9(4):351–60.
    58. Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N, et al. HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2- positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res. 2011;17(15):5132–9. 64. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 1997;389(6649):349–52.
    59. Jones RA, Campbell CI, Gunther EJ, Chodosh LA, Petrik JJ, Khokha R, et al. Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene. 2007;26(11):1636–44.
    60. Bolderson E, Richard DJ, Zhou BB, Khanna KK. Recent advances in cancer therapy targeting proteins involved in DNA doublestrand break repair. Clin Cancer Res. 2009;15(20):6314–20.
    61. Ashwell S, Zabludoff S. DNA damage detection and repair pathways--recent advances with inhibitors of checkpoint kinases in cancer therapy. Clin Cancer Res. 2008;14(13):4032–7.
    62. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70(5):2085–94.
    63. Sharpe R, Pearson A, Herrera-Abreu MT, Johnson D, Mackay A, Welti JC, et al. FGFR Signaling Promotes the Growth of Triple-Negative and Basal-Like Breast Cancer Cell Lines Both In Vitro and In Vivo. Clinical Cancer Research. 2011;17(16):5275–86.