Document Type : Review Article(s)

Authors

1 Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

2 Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

Breast cancer (BC) is a heterogeneous disease characterized by significant global mortality and incidence rates. Annually, approximately 1 million cases of BC are diagnosed worldwide, with over 170,000 classified as triple-negative. Triple-negative breast cancer (TNBC) is a particularly aggressive subtype lacking targeted therapeutic options, which contributes to poorer outcomes compared to other BC subtypes. The five-year survival rate for patients with TNBC is roughly 30% lower than that for patients with other subtypes. TNBC treatment options are limited to surgery, radiotherapy, and chemotherapy. There is a critical need for the development of targeted therapies. Enhancing early detection through effective diagnostic and prognostic biomarkers can significantly improve survival rates. This review explores recent advancements in clinically relevant proteomic, genetic, and metabolomic biomarkers for TNBC, highlighting their potential roles as prognostic, diagnostic, and predictive markers that could facilitate personalized treatment approaches.

Highlights

Zahra Roshanizadeh (PubMed)

Abbas Ghaderi (Google Scholar)

Keywords

Main Subjects

How to cite this article:

Roshanizadeh Z, Haghshenas MR, Ghaderi A. Triple-negative breast cancer: Emerging biomarkers for early diagnosis, prognosis, and treatment. Middle East J Cancer. 2024; 15(4):257-71. doi:10.30476/mejc. 2024.100755.1998.

  1. Cao J, Eshak ES, Liu K, Muraki I, Cui R, Iso H, et al. Television viewing time and breast cancer incidence for Japanese premenopausal and postmenopausal women: The JACC study. Cancer Res Treat. 2019;51(4):1509-17.doi: 10.4143/crt.2018.705.
  2. Changavi AA, Shashikala A, Ramji AS. Epidermal growth factor receptor expression in triple negative and nontriple negative breast carcinomas. J Lab Physicians. 2015;7 (2):79-83.doi: 10.4103/0974-2727.163129.
  3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi: 10.3322/caac.21492. Erratum in: CA Cancer J Clin. 2020;70(4):313.
  4. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2020;70(1):7-30.doi: 10.3322/caac.21590.
  5. Gnant M, Thomssen C, Harbeck N. St. Gallen/Vienna 2015: a brief summary of the consensus discussion. Breast Care (Basel). 2015;10(2):124-30. doi: 10.1159/000430488.
  6. Lehmann BD, Colaprico A, Silva TC, Chen J, An H, Ban Y, et al. Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes. Nat Commun. 2021;12(1):6276. doi: 10.1038/s41467-021-26502-6.
  7. Zhang Y, Wang Q, Yang WK, Wang YS, Zhou Q, Lin J, et al. Development of an immune-related prognostic biomarker for triple-negative breast cancer. Ann Med. 2022;54(1):1212-20. doi: 10.1080/07853890.2022.2067894.
  8. Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.doi: 10.1038/ncomms3612.
  9. Nederlof I, Horlings HM, Curtis C, Kok M. A High-dimensional window into the micro-environment of triple negative breast cancer. Cancers (Basel). 2021;13(2):316.doi: 10.3390/cancers13020316.
  10. Hamy AS, Pierga JY, Sabaila A, Laas E, Bonsang-Kitzis H, Laurent C, et al. Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer. Ann Oncol. 2017; 28(9): 2233-40. doi:10.1093/annonc/mdx309.
  11. Sharma P, Stecklein SR, Kimler BF, Sethi G, Petroff BK, Phillips TA, et al. The prognostic value of BRCA1 promoter methylation in early stage triple negative breast cancer. J Cancer Ther Res. 2014;3(2):1-11. doi: 10.7243/2049-7962-3-2.
  12. Sporikova Z, Koudelakova V, Trojanec R, Hajduch M. Genetic markers in triple-negative breast cancer. Clin Breast Cancer. 2018;18(5):e841-e850. doi: 10.1016/j.clbc.2018.07.023.
  13. Elwan A, Abdelrahman AE, Alnagar AA, Abdelhamid MI, Nawar N. Clinicopathological features and treatment challenges in triple negative breast cancer patients: a retrospective cohort study. Turk Patoloji Derg. 2021;37(2):121-9. doi: 10.5146/tjpath.2020.01516.
  14. Vagia E, Mahalingam D, Cristofanilli M. The landscape of targeted therapies in TNBC. Cancers (Basel). 2020;12(4):916.doi: 10.3390/cancers12040916.
  15. Fan M, Chen J, Gao J, Xue W, Wang Y, Li W, et al. Triggering a switch from basal- to luminal-like breast cancer subtype by the small-molecule diptoindonesin G via induction of GABARAPL1. Cell Death Dis. 2020;11(8):635. doi: 10.1038/s41419-020-02878-z.
  16. Bernhardt SM, Dasari P, Walsh D, Townsend AR, Price TJ, Ingman WV. Hormonal modulation of breast cancer gene expression: implications for intrinsic subtyping in premenopausal women. Front Oncol. 2016;6:241.doi:10.3389/fonc.2016.00241.
  17. Yin L, Duan JJ, Bian XW, Yu SC. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 2020; 22(61): 22-61. doi: 10.1186/s13058-020-01296-5.
  18. Yin L, Duan JJ, Bian XW, Yu SC. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 2020;22(1):61. doi: 10.1186/s13058-020-01296-5.
  19. Zhao S, Zuo WJ, Shao ZM, Jiang YZ. Molecular subtypes and precision treatment of triple-negative breast cancer. Ann Transl Med. 2020;8(7):499. doi: 10.21037/atm.2020.03.194.
  20. Singh DD, Yadav DK. TNBC: Potential targeting of multiple receptors for a therapeutic breakthrough, nanomedicine, and immunotherapy. Biomedicines. 2021;9(8):876. doi: 10.3390/biomedicines9080876.
  21. Lehmann BD, Colaprico A, Silva TC, Chen J, An H, Ban Y, et al. Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes. Nat Commun. 2021;12(1):6276. doi: 10.1038/s41467-021-26502-6.
  22. Zhao S, Zuo WJ, Shao ZM, Jiang YZ. Molecular subtypes and precision treatment of triple-negative breast cancer. Ann Transl Med. 2020; 8(7): 4. doi: 10.21037/atm.2.
  23. Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, et al. Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS One. 2016;11(6):e0157368.doi: 10.1371/journal.pone.0157368.
  24. Larsen DH, Hari F, Clapperton JA, Gwerder M, Gutsche K, Altmeyer M, et al. The NBS1-Treacle complex controls ribosomal RNA transcription in response to DNA damage. Nat Cell Biol. 2014;16(8):792-803. doi: 10.1038/ncb3007.
  25. Hu J, Lai Y, Huang H, Ramakrishnan S, Pan Y, Ma VWS, et al. TCOF1 upregulation in triple-negative breast cancer promotes stemness and tumour growth and correlates with poor prognosis. Br J Cancer. 2022;126(1):57-71. doi: 10.1038/s41416-021-01596-3.
  26. Walker AJ, Wedam S, Amiri-Kordestani L, Bloomquist E, Tang S, Sridhara R, et al. FDA approval of palbociclib in combination with fulvestrant for the treatment of hormone receptorepositive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2016;22:4968-72.doi: 10.1158/1078-0432.CCR-16-0493.
  27. Asghar US, Barr AR, Cutts R, Beaney M, Babina I, Sampath D, et al. Single-cell dynamics determines response to CDK4/6 inhibition in triple-negative breast cancer. Clin Cancer Res. 2017;23:5561-72. doi: 10.1158/1078-0432.CCR-17-0369.
  28. Liu T, Yu J, Deng M, Yin Y, Zhang H, Luo K, et al. CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1. Nat Commun. 2017;8:13923. doi: 10.1038/ncomms13923.
  29. Walker AJ, Wedam S, Amiri-Kordestani L, Bloomquist E, Tang S, Sridhara R, et al. FDA approval of palbociclib in combination with Fulvestrant for the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2016;22(20):4968-72. doi: 10.1158/1078-0432.CCR-16-0493.
  30. Rajput S, Khera N, Guo Z, Hoog J, Li S, Ma CX. Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer. Oncotarget. 2016;7:56864-75. doi: 10.18632/oncotarget.10870.
  31. Zhai X, Yang Z, Liu X, Dong Z, Zhou D. Identification of NUF2 and FAM83D as potential biomarkers in triple-negative breast cancer. PeerJ. 2020;8:e9975. doi: 10.7717/peerj.9975.
  32. Xu W, Wang Y, Wang Y, Lv S, Xu X, Dong X. Screening of differentially expressed genes and identification of NUF2 as a prognostic marker in breast cancer. Int J Mol Med. 2019;44(2):390-404. doi: 10.3892/ijmm.2019.4239.
  33. Wang Z, Liu Y, Zhang P, Zhang W, Wang W, Curr K, et al. FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7. Oncotarget. 2013;4:2476-86. doi: 10.18632/oncotarget.1581.
  34. Liu Y, Teng L, Fu S, Wang G, Li Z, Ding C, et al. Highly heterogeneous-related genes of triple-negative breast cancer: potential diagnostic and prognostic biomarkers. BMC Cancer. 2021;21:644. doi: 10.1186/s12885-021-08318-1.
  35. da Silva JL, Cardoso Nunes NC, Izetti P, de Mesquita GG, de Melo AC. Triple negative breast cancer: A thorough review of biomarkers. Crit Rev Oncol Hematol. 2020;145:102855. doi: 10.1016/j.critrevonc.2019.102855.
  36. Li RD, Wang Q, Yin BC. Enzyme-free detection of sequencespecific microRNAs based on nanoparticle-assisted signal amplification strategy. Biosens Bioelectron. 2016;77:995-1000. doi: 10.1016/j.bios.2015.10.082.
  37. Lü L, Mao X, Shi P, He B, Xu K, Zhang S, et al. MicroRNAs in the prognosis of triple-negative breast cancer: A systematic review and meta-analysis. Medicine (Baltimore). 2017;96(22):e7085. doi: 10.1097/MD.0000000000007085.
  38. Malla RR, Kumari S, Gavara MM, Badana AK, Gugalavath S, Kumar DKG, et al. A perspective on the diagnostics, prognostics, and therapeutics of microRNAs of triple-negative breast cancer. Biophys Rev. 2019;11(2):227-34. doi: 10.1007/s12551-019-00503-8.
  39. Adams BD, Wali VB, Cheng CJ, Inukai S, Booth CJ, Agarwal S, et al. miR-34a silences c-SRC to attenuate tumor growth in triple-negative breast cancer. Cancer Res. 2016;76(4):927-39. doi: 10.1158/0008-5472.CAN-15-2321.
  40. Imani S, Wu RC, Fu J. MicroRNA-34 family in breast cancer: from research to therapeutic potential. J Cancer. 2018;9(20):3765-75. doi: 10.7150/jca.25576.
  41. Kim Y, Ko JY, Lee SB, Oh S, Park JW, Kang HG, et al. Reduced miR-371b-5p expression drives tumor progression via CSDE1/RAC1 regulation in triple-negative breast cancer. Oncogene. 2022;41:3151-61.doi: 10.1038/s41388-022-02326-6.
  42. Zhang K, Luo Z, Zhang Y, Song X, Zhang L, Wu L, et al. Long non-coding RNAs as novel biomarkers for breast cancer invasion and metastasis. Oncol Lett. 2017;14(2):1895-904. doi: 10.3892/ol.2017.6462.
  43. Sakthianandeswaren A, Liu S, Sieber OM. Long noncoding RNA LINP1: scaffolding non-homologous end joining. Cell Death Discov. 2016;2:16059. doi: 10.1038/cddiscovery.2016.59.
  44. Shi F, Xiao F, Ding P, Qin H, Huang R. Long noncoding RNA highly up-regulated in liver cancer predicts unfavorable outcome and regulates metastasis by MMPs in triple-negative breast cancer. Arch Med Res. 2016;47(6):446-53.doi: 10.1016/j.arcmed.2016.11.001.
  45. Bai X, Zhang S, Qiao J, Xing X, Li W, Zhang H, et al. Long non‑coding RNA SChLAP1 regulates the proliferation of triple negative breast cancer cells via the miR‑524‑5p/HMGA2 axis. Mol Med Rep. 2021;23(6):446. doi: 10.3892/mmr.2021.12085.
  46. Xiao MS, Ai Y, Wilusz JE. Biogenesis and functions of circular RNAs come into focus. Trends Cell Biol. 2020;30(3):226-40. doi: 10.1016/j.tcb.2019.12.004.
  47. Darbeheshti F, Zokaei E, Mansoori Y, Allahyari SE, Kamaliyan Z, Kadkhoda S, et al. Circular RNA hsa_circ_0044234 as distinct molecular signature of triple negative breast cancer: a potential regulator of GATA3. Cancer Cell Int. 2021;21:312. doi: 10.1186/s12935-021-02015-6.
  48. Yang SJ, Wang DD, Zhong SL, Chen WQ, Wang FL, Zhang J, et al. Tumor-derived exosomal circPSMA1 facilitates the tumorigenesis, metastasis, and migration in triple-negative breast cancer (TNBC) through miR-637/Akt1/β-catenin (cyclin D1) axis. Cell Death Dis. 2021;12(5):420. doi: 10.1038/s41419-021-03680-1.
  49. Li L, Zheng X, Zhou Q, Villanueva N, Nian W, Liu X, et al. Metabolomics-based discovery of molecular signatures for triple negative breast cancer in Asian female population. Sci Rep. 2020;10(1):370. doi: 10.1038/s41598-019-57068-5.
  50. Schmidt DR, Patel R, Kirsch DG, Lewis CA, Vander Heiden MG, Locasale JW. Metabolomics in cancer research and emerging applications in clinical oncology. CA Cancer J Clin. 2021;71(4):333-58. doi: 10.3322/caac.21670.
  51. Pralea IE, Moldovan RC, Țigu AB, Ionescu C, Iuga CA. Mass spectrometry-based omics for the characterization of triple-negative breast cancer bio-signature. J Pers Med. 2020;10(4):277. doi: 10.3390/jpm10040277.
  52. Beatty A, Fink LS, Singh T, Strigun A, Peter E, Ferrer CM, et al. Metabolite profiling reveals the glutathione biosynthetic pathway as a therapeutic target in triple-negative breast cancer. Mol Cancer Ther. 2018;17(1):264-75.doi: 10.1158/1535-7163.MCT-17-0407.
  53. Cao MD, Lamichhane S, Lundgren S, Bofin A, Fjøsne H, Giskeødegård GF, et al. Metabolic characterization of triple negative breast cancer. BMC Cancer. 2014;14:941. doi: 10.1186/1471-2407-14-941.
  54. Kanaan YM, Sampey BP, Beyene D, Esnakula AK, Naab TJ, Ricks-Santi LJ, et al. Metabolic profile of triple-negative breast cancer in African-American women reveals potential biomarkers of aggressive disease. Cancer Genomics Proteomics. 2014;11(6):279-94. PMID: 25422359.
  55. Song Y, Zhao B, Xu Y, Ren X, Lin Y, Zhou L, et al. Prognostic significance of branched-chain amino acid transferase 1 and CD133 in triple-negative breast cancer. BMC Cancer. 2020;20:584. doi: 10.1186/s12885-020-07070-2.
  56. Kim JH, Jung SM, Shin JG, Cheong HS, Seo JM, Kim DY, et al. Potential association between ITPKC genetic variations and Hirschsprung disease. Mol Biol Rep. 2017;44:307-13. doi: 10.1007/s11033-017-4111-6.
  57. Oshi M, Newman S, Murthy V, Tokumaru Y, Yan L, Matsuyama R, et al. ITPKC as a prognostic and predictive biomarker of neoadjuvant chemotherapy for triple negative breast cancer. Cancers (Basel). 2020;12(10):2758. doi: 10.3390/cancers12102758.
  58. Gandhi S, Elkhanany A, Oshi M, Dai T, Opyrchal M, Mohammadpour H, et al. Contribution of immune cells to glucocorticoid receptor expression in breast cancer. Int J Mol Sci. 2020;21(13).doi: 10.3390/ijms21134635.
  59. Antonioli L, Blandizzi C, Malavasi F, Ferrari D, Haskób G. Anti-CD73 immunotherapy: a viable way to reprogram the tumor microenvironment. Oncoimmunology. 2016;5(9):e1216292.doi: 10.1080/2162402X.2016.1216292.
  60. Allard D, Turcotte M, Stagg J. Targeting A2 adenosine receptors in cancer. Immunol Cell Biol. 2017;95(4):333-9.doi: 10.1038/icb.2017.8.
  61. Buisseret L, Pommey S, Allard B, Garaud S, Bergeron M, Cousineau I, et al. Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial. Ann Oncol. 2018;29(4):1056-62. doi: 10.1093/annonc/mdx730.
  62. Dutta P, Sarkissyan M, Paico K, Wu Y, Vadgama JV. MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis. Breast Cancer Res Treat. 2018;170(3):477-86. doi: 10.1007/s10549-018-4760-8.
  63. Raghu G, Martinez FJ, Brown KK, Costabel U, Cottin V, Wells AU, et al. CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab. Eur Respir J. 2015; 46(6):1740-50. doi:10.1183/13993003.01558-2014.
  64. Park G, Kim J. Myeloid differentiation primary response gene 88-leukotriene B4 receptor 2 cascade mediates lipopolysaccharide-potentiated invasiveness of breast cancer cells. Oncotarget. 2015;6:5749-59.doi: 10.18632/oncotarget.3304.
  65. Weng MS, Chang JH, Hung WY, Yang YC, Chien MH. The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance. J Exp Clin Cancer Res. 2018;37(1):61. doi: 10.1186/s13046-018-0728-0.
  66. Evani SJ, Prabhu RG, Gnanaruban V, Finol EA, Ramasubramanian AK. Monocytes mediate metastatic breast tumor cell adhesion to endothelium under flow. FASEB J. 2013;27(8):3017-29. doi: 10.1096/fj.12-224824.
  67. Ilie SM, Bacinschi XE, Botnariuc I, Anghel RM. Potential clinically useful prognostic biomarkers in triple-negative breast cancer: preliminary results of a retrospective analysis. Breast Cancer (Dove Med Press). 2018;10:177-94. doi: 10.2147/BCTT.S175556.
  68. Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem.2001;276(21):18563-9.doi: 10.1074/jbc.M010787200.
  69. Witton CJ, Hawe SJK, Cooke TG, Bartlett JMS. Cyclooxygenase 2 (COX2) expression is associated with poor outcome in ER-negative, but not ER-positive, breast cancer. Histopathology. 2004;45(1):47-54.doi: 10.1111/j.1365-2559.2004.01898.x.
  70. Krishnamachary B, Stasinopoulos I, Kakkad S, Penet MF, Jacob D, Wildes F, et al. Breast cancer cell cyclooxygenase-2 expression alters extracellular matrix structure and function and numbers of cancer associated fibroblasts. Oncotarget. 2017;8(11):17981-94.doi: 10.18632/oncotarget.
  71. Gharib F, Zamzam Y, Sad LM. Role of COX-2 inhibitors as maintenance therapy in non-metastatic triple negative breast cancer Egyptian patients, single institution study. Oncology and Radiotherapy. 2020;1(52):1-6.
  72. Nonneville Ad, ScilitPreprints, Finetti P, Adelaide J, Lambaudie É, Viens P, et al. A tyrosine kinase expression signature predicts the post-operative clinical outcome in triple negative breast cancers. Cancers. 2019;11(8):1158. doi: 10.3390/cancers11081158.
  73. M-Rabet M, Cabaud O, Josselin E, Finetti P, Castellano R, Farina A, et al. Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer. Ann Oncol. 2017;28(4):769-76. doi: 10.1093/annonc/mdw678.
  74. Zeindler J, Soysal SD, Piscuoglio S, Ng CKY, Mechera R, Isaak A, et al. Nectin-4 expression is an independent prognostic biomarker and associated with better survival in triple-negative breast cancer. Front Med (Lausanne). 2019;6:200. doi: 10.3389/fmed.2019.00200.
  75. Fathi E, Yarbro JM, Homayouni R. NIPSNAP protein family emerges as a sensor of mitochondrial health. Bioessays. 2021; 43(6): e2100014. doi: 10.1002/bies.202100014.
  76. Abudu YP, Pankiv S, Mathai BJ, Esguerra CV, Johansen T, Simonsen A. NIPSNAP1 and NIPSNAP2 act as ‘‘Eat Me’’ signals for mitophagy. Developmental Cell. 2019; 49: 509-25. doi: 10.1016/j.devcel.2019.03.013.
  77. Block CJ, Mitchell AV, Wu L, Glassbrook J, Craig D, Chen W, et al. RNA binding protein RBMS3 is a common EMT effector that modulates triple-negative breast cancer progression via stabilizing PRRX1 mRNA. Oncogene. 2021;40(46):1-13. doi: 10.1038/s41388-021-02030-x.
  78. Pilotte J, Kiosses W, Chan SW, Makarenkova HP, Dupont-Versteegden E, Vanderklish PW. Morphoregulatory functions of the RNA-binding motif protein 3 in cell spreading, polarity and migration. Sci Rep. 2018;8:7367. doi: 10.1038/s41598-018-25668-2.
  79. Auñon PZ, Adrián SG, Trilla-Fuertes L, Gámez-Pozo A, Prado-Vázquez G, Zapater-Moros A, et al. Abstract P3-08-42: Disease-free survival prognostic signature in triple-negative breast cancer based on high-throughput proteomics data. Cancer Res. 2020;80(4_Supplement):P3-08-42. doi:10.1158/1538-7445.SABCS19-P3-08-42.
  80. Wang Y, Lee YM, Baitsch L, Huang A, Xiang Y, Tong H, et al. MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. Elife. 2014;3:e01763. doi: 10.7554/eLife.01763. Erratum in: Elife. 2018;7.
  81. Speers C, Zhao SG, Kothari V, Santola A, Liu M, Wilder-Romans K, et al. Maternal embryonic leucine zipper kinase (MELK) as a novel mediator and biomarker of radioresistance in human breast cancer. Clin Cancer Res. 2016;22(23):5864-75. doi: 10.1158/1078-0432.CCR-15-2711.
  82. Kim SH, Joshi K, Ezhilarasan R, Myers TR, Siu J, Gu Cet al. EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner. Stem Cell Reports. 2015;4(2):226-38. doi: 10.1016/j.stemcr.2014.12.006.
  83. Speers C, Tsimelzon A, Sexton K, Herrick AM, Gutierrez C, Culhane A, et al. Identification of novel kinase targets for the treatment of estrogen receptornegative breast cancer. Clin Cancer Res.2009;15:6327-40.doi: 10.1158/1078-0432.CCR-09-1107.
  84. Ji W, Arnst C, Tipton AR, Bekier ME 2nd, Taylor WR, Yen TJ, et al. OTSSP167 abrogates mitotic checkpoint through inhibiting multiple mitotic kinases. PLoS One. 2016;11(4):e0153518. doi: 10.1371/journal.pone.0153518.
  85. Moreno CS. MELK kinase holds promise as a new radiosensitizing target and biomarker in triple-negative breast cancer. J Thorac Dis. 2016;8(10):E1367-E8.doi: 10.21037/jtd.2016.10.40.
  86. Wang C, Gao C, Meng K, Qiao H, Wang Y. Human adipocytes stimulate invasion of breast cancer MCF-7 cells by secreting IGFBP-2. PLoS One. 2015;10(3):e0119348. doi:10.1371/journal.pone.0119348.
  87. Fleisher B, Clarke C, Ait-Oudhia S. Current advances in biomarkers for targeted therapy in triple-negative breast cancer. Breast Cancer (Dove Med Press). 2016;8:183-97. doi: 10.2147/BCTT.S114659.
  88. Martin JL, Silva HCd, Lin MZ, Scott CD, Baxter RC. Inhibition of insulin-like growth factor-binding protein-3 signaling through sphingosine kinase-1 sensitizes triple-negative breast cancer cells to EGF receptor blockade. Mol Cancer Ther. 2014;13(2):316-28. doi: 10.1158/1535-7163.MCT-13-0367.
  89. Hernandez BY, Wilkens LR, Marchand LL, Horio D, Chong CD, Loo LWM. Differences in IGF-axis protein expression and survival among multiethnic breast cancer patients. Cancer Med. 2015;4(3):354-62.doi: 10.1002/cam4.375.
  90. 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. doi: 10.1111/j.1365-2559.2011.03884.x.
  91. Kim SJ, Kim YS, Jang ED, Seo KJ, Kim JS. Prognostic impact and clinicopathological correlation of CD133 and ALDH1 expression in invasive breast cancer. J Breast Cancer. 2015;18(4):347-55. doi: 10.4048/jbc.2015.18.4.347.