Understanding triple negative breast cancer: A review on molecular signaling pathways
Abstract
Triple negative breast cancer (TNBC) is a divergent disease which lacks receptor for estrogen (ER), progesterone (PR) and human epidermal growth factor receptor 2 (HER2). It constitutes about 15-20% of total breast cancer cases globally which mainly strikes younger women. Due to its aggressive nature, the standard choice of treatment for TNBC is chemotherapy, but the same has very poor prognosis due to risk of tumor recurrence, metastasis and death. To direct the line of research to get pathological Complete Response (pCR) and increase the quality of life (QOL) years of cancer patients, it is necessary to understand the molecular pathways and their down signalling pathways which can be targeted. Triple negative breast cancer involves several signaling pathways leading to tumor initiation, proliferation, and metastasis such as Ras/Raf/MEK pathway, PI3/AKT/mTOR pathway, DNA repair pathway, Wnt/β-catenin Pathway, Hedgehog pathway, Notch signalling pathway and immune pathway. Currently available treatment for triple negative breast cancer comprises chemotherapy in combination which includes anthracyclines, platinum compounds, folate antagonist, taxanes, cyclophosphamide and others. The present review focuses on the molecular aspect of TNBC subtypes and targets. Also, the ongoing clinical trials along with the completed clinical trials targeting different pathways for the treatment of TNBC patients are discussed.
Keywords:
Triple negative breast cancer, TNBC subtypes, molecular targets, signalling pathway, chemotherapy, clinical trialsDOI
https://doi.org/10.25004/IJPSDR.2022.140220References
Ahn SG, Kim SJ, Kim C, Jeong J. Breast Cancer Molecular Classification of Triple-Negative Breast Cancer. 2016;19:223–30.
Aksamitiene E, Kiyatkin A, Kholodenko BN. Cross-talk between mitogenic Ras / MAPK and survival PI3K / Akt pathways : a fine balance. 2012;139–46.
Andreopoulou E, Sparano JA. Chemotherapy in Patients with Anthracycline- and Taxane- Pretreated Metastatic Breast Cancer: An Overview. Curr Breast Cancer Rep. 2013;5:42–50.
Antonarakis ES, Heath EI, Smith DC, Rathkopf D, Blackford AL, Danila DC, et al. Repurposing Itraconazole asaTreatment for AdvancedProstate Cancer:ANoncomparativeRandomizedPhase II Trial inMenWith Metastatic Castration-Resistant Prostate Cancer. The Oncologist. 2013;18:163–73.
Aysola K, Desai A, Welch C, et al. Triple Negative Breast Cancer - An Overview. Hereditary Genet. 2013;2013(Suppl 2):001. Available from: doi:10.4172/2161-1041.S2-001
Balko JM, Giltnane JM, Wang K, Schwarz LJ, Christian D, Cook RS, et al. Molecular profiling of the residual disease of triple-negative breast cancers af ter neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov. 2014;4:232–45.
Bauer JA, Chakravarthy AB, Rosenbluth JM, Mi D, Erin H, Granja-ingram NDM, et al. Identification of Markers of Taxane Sensitivity Using Proteomic and Genomic Analyses of Breast Tumors from Patients Receiving Neoadjuvant Paclitaxel and Radiation. Clinical Cancer Research. 2011;16:681–90.
Belani CP, Dahlberg SE, Rudin CM, Fleisher M, Chen HX, Takebe N, et al. Vismodegib or Cixutumumab in Combination With Standard Chemotherapy for Patients With Extensive-Stage Small Cell Lung Cancer: A Trial of the ECOG-ACRIN Cancer Research Group (E1508). Cancer. 2016;122:2371–8.
Berlin J, Bendell JC, Hart LL, Firdaus I, Gore I, Hermann RC, et al. A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer. 2013;19:258–68.
Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple- Negative Breast Cancer: Challenges and Opportunities of a Heterogeneous Disease. Nature Publishing Group. 2016;13(11):674- 690. Available from: doi: 10.1038/nrclinonc.2016.66.
Borg J, Belotti E, Daulat A, Lembo F, Bertucci F, Charafe-Jauffret E. Deregulation of the non-canonical pathway in triple-negative breast cancer. FASEB J. 2013;27:610.1-1. Available from: https:// doi.org/10.1096/fasebj.27.1_supplement.610.1.
Cancer Today [Internet]. World Health Organization. 2020. Available from https://gco.iarc.fr/today/online-analysis-multi-bars?v=2020&mode=cancer&mode_population=countries&pop ulation=900&populations=900&key=asr&sex=2&cancer=39&t ype=0&statistic=5&prevalence=0&population_group=0&ages_ group%5B%5D=0&ages_group%5B%5D=17&nb_items=10& [Last accessed date: 2021-02-15].
Chakravarthy AB, Kelley MC, Mclaren B, Truica CI, Billheimer D, Mayer IA, et al. Cancer Therapy : Clinical Neoadjuvant Concurrent Paclitaxel and Radiation in Stage II / III Breast Cancer. 2006;12:1570–7.
Chamorro MN, Schwartz DR, Vonica A, Brivanlou AH, Cho KR, Varmus HE. FGF-20 and DKK1 are transcriptional targets and development. 2005;24(1):73-84. Available from: doi: 10.1038/ sj.emboj.7600460.
ClinicalTrials.gov. [Internet]. Bethesda (MD): U.S. National Library of Medicine. 2022. Available from: https://www.clinicaltrials.gov/
Collignon J, Lousberg L, Schroeder H, Jerusalem G. Triple-negative breast cancer : treatment challenges and solutions. Breast Cancer: Targets and Therapy. 2016;8:93–107.
Cousineau I, Belmaaza A. BRCA1-truncating Mutation , Deregulates Homologous Recombination ND ES SC Key words RIB. Cell Cycle. 2007;6:962–71.
Craig DW, Shaughnessy JAO, Kiefer JA, Aldrich J, Sinari S, Moses TM, et al. Genome and Transcriptome Sequencing in Prospective Metastatic Triple-Negative Breast Cancer Uncovers Therapeutic Vulnerabilities. 2013;12:104–17.
De A. Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim Biophys. 2011;43:745–56.
Dejmek J, Sa A, Nielsen CK, Andersson T, Leandersson K. Wnt-5a / Ca2+-Induced NFAT Activity Is Counteracted by Wnt-5a / Yes-Cdc42- Casein Kinase 1alpha Signaling in Human Mammary Epithelial Cells. 2006;26:6024–36. Available from: doi: 10.1128/MCB.02354-05.
Denkert C, Von Minckwitz G, Brase JC, Sinn B V., Gade S, Kronenwett R, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. Journal of Clinical Oncology. 2015;33:983–91.
Dufraine J, Funahashi Y, Kitajewski J. Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene. 2014;27:5132–7.
ElShamy WM. The protective ef fect of longer duration of breastfeeding against pregnancy-associated triple negative breast cancer. Oncotarget. 2016;7(33):53941-53950. Available from: doi:10.18632/oncotarget.9690
Geyer FC, Lacroix-triki M, Savage K, Arnedos M, Lambros MB, Mackay A, et al. b -Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Modern Pathology. 2010;24:209–31.
Giltnane JM, Balko JM. Rationale for Targeting the Ras / MAPK Pathway in Triple-Negative Breast Cancer. Discovery Medicine. 2014;
Gingras A, Raught B, Sonenberg N. Regulation of translation initiation by FRAP / mTOR. 2001;15(7):807-26. Available from: doi: 10.1101/gad.887201.
Gomez-Orte E, Saenz-Narciso B, Moreno S, Cabello J. Multiple functions of the noncanonical Wnt pathway. Trends Genet. 2013;29:545–53.
Habas R, Kato Y, He X. Wnt / Frizzled Activation of Rho Regulates Vertebrate Gastrulation and Requires a Novel Formin Homology Protein Daam1. 2001;107:843–54.
Habib JG, O’Shaughnessy JA. The hedgehog pathway in triple-negative breast cancer. Cancer Medicine. 2016;5:2989–3006.
Hartman A, Ford J. BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nat Genet. 2002;32:180–4.
He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa L., et al. Identification of c- MYC as a target of the APC pathway. Science. 1998;281:1509–12.
Hoeflich KP, Brien CO, Boyd Z, Cavet G, Guerrero S, Jung K, et al. Cancer Therapy : Preclinical In vivo Antitumor Activity of MEK and Phosphatidylinositol 3-Kinase Inhibitors in Basal-Like Breast Cancer Models. 2009;15:4649–65.
Hurley JH, Misra S. Signaling and subcellular targeting by membrane-binding domains 1. Annu Rev Biophys Biomol Struct. 2000;29:49–79.
Ishitani T, Ninomiya-tsuji J, Matsumoto K. Regulation of Lymphoid Enhancer Factor 1/T-Cell Factor by Mitogen-Activated Protein Kinase-Related Nemo-Like Kinase-Dependent Phosphorylation in Wnt/β-Catenin Signaling. 2003;23:1379–89.
Jacquemier J, Bertucci F, Finetti P, Esterni B, Charafe-Jauffret E, Thibult ML, et al. High expression of indoleamine 2,3-dioxygenase in the tumour is associated with medullary features and favourable outcome in basal-like breast carcinoma. International Journal of Cancer. 2012;130:96–104.
Jamdade VS, Sethi N, Mundhe NA, Kumar P, Lahkar M, Sinha N. Therapeutic targets of triple-negative breast cancer : a review Tables of Links. 2015;172(17):4228-37. Available from: doi: 10.1111/ bph.13211.
Jang G, Hong I, Kim R, Lee S, Park S, Lee E, et al. Wnt / b -Catenin Small-Molecule Inhibitor CWP232228 Preferentially Inhibits the Growth of Breast Cancer Stem-like Cells. 2015;75(8):1691-702. Available from: doi: 10.1158/0008-5472.CAN-14-2041.
Jimenez C, Hernandez C, Pimentel B, Carrera AC. The p85 Regulatory Subunit Controls Sequential Activation of Phosphoinositide 3-Kinase by Tyr Kinases and Ras. The journal of biological chemistry. 2002;277:41556–62.
Khramtsov AI, Khramtsova GF, Tretiakova M, Huo D, Olopade OI, Goss KH. Wnt /  -Catenin Pathway Activation Is Enriched in Basal- Like Breast Cancers and Predicts Poor Outcome. 2010;176:2911–20.
Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons K V, et al. Itraconazole, a commonly used anti-fungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2014;17:388–99.
Lehmann BD, Jovanović B, Chen X, et al. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One. 2016;11(6):e0157368. Published 2016 Jun 16. Available from: doi:10.1371/journal.pone.0157368
Lehmann BDB, Bauer J a J, 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. Journal of Clinical Investigation. 2011;121:2750–67.
Li L, Yuan H, Xie W, Mao J, Caruso AM, Mcmahon A, et al. Dishevelled Proteins Lead to Two Signaling Pathways. 1999;274:129–34.
Lips EH, Mulder L, Oonk A, Kolk LE Van Der, Hogervorst FBL, Imholz ALT, et al. Triple-negative breast cancer : BRCAness and concordance of clinical features with BRCA1-mutation carriers. British Journal of Cancer. 2013;108:2172–7.
Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer. Nat Rev Drug Discov. 2009;8:627–44.
Maeda T, Masayuki H, Jin C, Rajabi H, Tagde A, Alam M, et al. MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer. Cancer Research. 2018;78(1):205-215. Available from: doi: 10.1158/0008-5472.CAN-17-1636.
Manning BD, Cant ley LC. AKT/PKB Signaling: Navigat ing Downstream. Cell. 2007;129:1261–74.
Marra A. Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies. npj Breast Cancer. 2020;6:1–16. Available from: doi: 10.1038/s41523-020-00197-2.
Montagut C, Settleman J. Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Letter. 2009;283:125–34.
Mora A, Komander D, Van Aalten D, Alessi D. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 2004;15:161–70.
Moynahan ME, Pierce AJ, Jasin M. BRCA2 Is Required for Homology- Directed Repair of Chromosomal Breaks. 2001;7:263–72.
Noguera-Troise I, Daly C, Papadopoulos N, Coetzee S, Boland P, Gale N. Blockade of Dll4 inhibits tumor growth by promoting non-productive angiogenesis. Nature. 2006;444:1032–7.
Paplomata E, Regan RO. The PI3K / AKT / mTOR pathway in breast cancer : targets , trials and biomarkers. 2014;6(4): 154–166. Available from: doi: 10.1177/1758834014530023.
Parinyanitikul N, Blumenschein GR, Wu Y, Lei X, Chavez- MM, Smart M, et al. Mesothelin expression and survival outcomes in triple receptor negative breast cancer. Clin Breast Cancer. 2013;13(5):378- 84. Available from: doi: 10.1016/j.clbc.2013.05.001.
Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, et al. WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci USA. 1998;95:14717–22.
Peshkin BN, Alabek ML, Isaacs C. BRCA1/2 Mutations and Triple Negative Breast Cancers. Breast Dis. 2010;32(1-2):25-33. Available from: doi: 10.3233/BD-2010-0306.
Pohl S, Brook N, Agostino M, Arfuso F, Kumar AP, Dharmarajan A. Wnt signaling in triple-negative breast cancer. 2017;6, e310. Available from: https://doi.org/10.1038/oncsis.2017.14
Polkinghorn W, Tarbell N. Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol. 2007;4:295–304.
Powell SN, Kachnic LA. Roles of BRCA1 and BRCA2 in homologous recombination , DNA replication fidelity and the cellular response to ionizing radiation. 2003;22(37):5784-91. Available from: doi: 10.1038/sj.onc.1206678.
Previs RA, Coleman RL, Harris AL, Sood AK. Molecular Pathways : Translational and Therapeutic Implications of the Notch Signaling Pathway in Cancer. 2015;21(5):955-61. Available from: doi: 10.1158/1078-0432
Raghavendra A, Kalita-de Croft P, Vargas AC, Smart CE, Simpson PT, Saunus JM, et al. Expression of MAGE-A and NY-ESO-1 cancer/ testis antigens is enriched in triple-negative invasive breast cancers. Histopathology. 2018;73:68–80.
Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I et al. Vismodegib exerts targeted efficacy against recurrent sonic hedgehog - Subgroup medulloblastoma: Results from phase II Pediatric Brain Tumor Consortium studies PBTC-025B and PBTC- 032. Journal of Clinical Oncology. 2015;33(24):2646-2654. Available from: https://doi.org/10.1200/JCO.2014.60.1591
Roymans D, Slegers H. Phosphat idylinositol 3-kinases in tumor progression. 2001;268(3):487-98. Available from: doi: 10.1046/j.1432-1327.2001.01936.x.
Schu U, Zhao Q, Godinho SA, Heine VM, Medema H, Pellman D, et al. Forkhead Transcription Factor FoxM1 Regulates Mitotic Entry and Prevents Spindle Defects in Cerebellar Granule Neuron Precursors. 2007;27(23):8259-70. Available from: doi: 10.1128/MCB.00707-07.
Sharma P. Biology and Management of Patients With Triple-Negative Breast Cancer. The Oncologist. 2016;21:1050–62.
Shi Y, Jin J, Ji W, Guan X. Therapeutic landscape in mutational triple negative breast cancer. 2018;17(99). Available from: https://doi. org/10.1186/s12943-018-0850-9
Shih I, Wang T. Notch Signaling,γ-Secretase Inhibitors, and Cancer Therapy Inhibitors , and Cancer Therapy. Cancer Res. 2007;67:1879–83.
Stagg J, Allard B. Immunotherapeutic approaches in triple-negative breast cancer: Latest research and clinical prospects. Therapeutic Advances in Medical Oncology. 2013;5:169–81.
Stoppa-lyonnet D. The biological effects and clinical implications of BRCA mutations : where do we go from here ? 2016;24 Suppl 1(Suppl 1):S3-9. Available from: doi: 10.1038/ejhg.2016.93.
Summa S De, Pinto R, Sambiasi D, Petriella D, Paradiso V, Paradiso A, et al. BRCAness : a deeper insight into basal-like breast tumors. 2013;24 Suppl 8:viii13-viii21. Available from: doi: 10.1093/annonc/ mdt306.
Teh M, Wong S, Neill GW, Ghali LR, Philpott MP, Quinn AG. FOXM1 Is a Downstream Target of Gli1 in Basal Cell Carcinomas 1. 2002;62(16):4773-80.
Tentori L, Graziani G. Chemopotentiation by PARP inhibitors in cancer therapy. Pharm Res. 2005;52:25–33.
Tentori L, Porarena I, Graziani G. Potential clinical applications of poly (ADP-ribose) polymerase inhibitors. Pharm Res. 2002;45:73– 85.
Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–6.
Turner NC, Reis-filho JS. Basal-like breast cancer and the BRCA1 phenotype. 2006;25(43):5846-53. Available from: doi: 10.1038/ sj.onc.1209876.
Vivanco I, Sawyers C. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.
Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne WC, Marsters JC Jr, de Sauvage FJ, Low JA. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361(12):1164-72. Available from: doi: 10.1056/ NEJMoa0905360.
Wallace MD, Pfefferle AD, Shen L, McNairn AJ, Cerami EG, Fallon BL, et al. Comparative Oncogenomics Implicates the Neurofibromin 1 Gene (NF1) as a Breast Cancer Driver. Genetics. 2012;192:385–96.
Wee P, Wang Z. Epidermal Growth Factor Receptor Cell Proliferation. Cancers (Basel). 2017 May; 9(5): 52. Available from: doi: 10.3390/ cancers9050052
White M. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem. 1998;182:3–11.
Wismar J, Habtemichael N, Warren JT, Dai J, Gilbert LI, Gateff E. The Mutation without children rgl Causes Ecdysteroid Deficiency in Third-Instar Larvae of Drosophila melanogaster. 2000;17:1–17.
Xie Y, Gou Q, Wang Q, Zhong X, Zheng H. The role of BRCA status on prognosis in patients with triple- negative breast cancer. 2017;8:87151–62.
Xu W, Yang Z, Lu N. A new role for the PI3K / Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adhesion & Migration. 2015;9:317–24.
Zhang J, Powell SN. The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair. 2005;3:531–40.
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