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Molecular targets and therapeutic strategies for triple-negative breast cancer

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Abstract

Triple-negative breast cancer (TNBC) is known for its heterogeneous complexity and is often difficult to treat. TNBC lacks the expression of major hormonal receptors like estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 and is further subdivided into androgen receptor (AR) positive and AR negative. In contrast, AR negative is also known as quadruple-negative breast cancer (QNBC). Compared to AR-positive TNBC, QNBC has a great scarcity of prognostic biomarkers and therapeutic targets. QNBC shows excessive cellular growth and proliferation of tumor cells due to increased expression of growth factors like EGF and various surface proteins. This study briefly reviews the limited data available as protein biomarkers that can be used as molecular targets in treating TNBC as well as QNBC. Targeted therapy and immune checkpoint inhibitors have recently changed cancer treatment. Many studies in medicinal chemistry continue to focus on the synthesis of novel compounds to discover new antiproliferative medicines capable of treating TNBC despite the abundance of treatments currently on the market. Drug repurposing is one of the therapeutic methods for TNBC that has been examined. Moreover, some additional micronutrients, nutraceuticals, and functional foods may be able to lower cancer risk or slow the spread of malignant diseases that have already been diagnosed with cancer. Finally, nanomedicines, or applications of nanotechnology in medicine, introduce nanoparticles with variable chemistry and architecture for the treatment of cancer. This review emphasizes the most recent research on nutraceuticals, medication repositioning, and novel therapeutic strategies for the treatment of TNBC.

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Abbreviations

BC:

Breast cancer

TNBC:

Triple-negative breast cancer

QNBC:

Quadruple-negative breast cancer

AR:

Androgen receptor

ER:

Estrogen receptor

PR:

Progesterone receptor

HER2:

Human epidermal growth factor receptor-2

EGFR:

Epidermal growth factor receptor

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

TLE3:

Transducer-like enhancer of split-3

PARP:

Poly-ADP-ribose polymerase

CAF:

Cancer-associated fibroblasts

LAG-3:

Lymphocyte activation gene-3

PD:

Programmed cell death

SKP2:

S-phase kinase-associated protein-2

TOPO2A:

Topoisomerase II-α

VEGFR2:

Vascular endothelial growth factor receptor-2

FGF:

Fibroblastic growth factor

PDGFα:

Platelet-derived growth factor-α

HIF-1:

Hypoxia-induced factor-1

TF:

Transcription factor

CAIX:

Carbonic anhydrase IX

TS:

Thymidylate synthase

TAM:

Tumor-associated macrophages

TAN:

Tumor-associated neutrophils

CDK:

Cyclin-dependent kinase

CERK:

Ceramide kinase

ACSL4:

Fatty-acyl CoA synthetase-4

TME:

Tumor microenvironment

References

  1. He Y, Jiang Z, Chen C, Wang X (2018) Classification of triple-negative breast cancers based on immunogenomic profiling. J Exp Clin Cancer Res 37(1):327. https://doi.org/10.1186/s13046-018-1002-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Investig 121(7):2750–2767. https://doi.org/10.1172/JCI45014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Doane AS, Danso M, Lal P, Donaton M, Zhang L, Hudis C, Gerald WL (2006) An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene 25(28):3994–4008. https://doi.org/10.1038/sj.onc.1209415

    Article  CAS  PubMed  Google Scholar 

  4. Hon JD, Singh B, Sahin A, Du G, Wang J, Wang VY, Deng FM, Zhang DY, Monaco ME, Lee P (2016) Breast cancer molecular subtypes: from TNBC to QNBC. Am J Cancer Res 6(9):1864–1872

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Angajala A, Hughley R, Shweta T, Dean-Colomb W, Tan M, Yates C (2018) Abstract A04: identification of differentially expressed micro-RNAs. In: Cancer Epidemiology, Biomarkers and Prevention A. Bhattarai et al (eds) Breast cancer research 22:127 page 8 of 11 American women with quadruple-negative breast cancer, 27(7 Supplement):A04-A

  6. Bonnefoi H, Grellety T, Tredan O, Saghatchian M, Dalenc F, Mailliez A, L’Haridon T, Cottu P, Abadie-Lacourtoisie S, You B, Mousseau M, Dauba J, Del Piano F, Desmoulins I, Coussy F, Madranges N, Grenier J, Bidard FC, Proudhon C et al (2016) A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor-positive locally advanced or metastatic breast cancer (UCBG 12–1). Ann Oncol 27(5):812–818. https://doi.org/10.1093/annonc/mdw067

    Article  CAS  PubMed  Google Scholar 

  7. Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, Stearns V, Doane AS, Danso M, Moynahan ME, Momen LF, Gonzalez JM, Akhtar A, Giri DD, Patil S et al (2013) Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res 19(19):5505–5512. https://doi.org/10.1158/1078-0432.CCR-12-3327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O’Shaughnessy J, Gradishar W, Schmid P, Winer E, Kelly C, Nanda R, Gucalp A, Awada A, Garcia-Estevez L, Trudeau ME, Steinberg J, Uppal H, Tudor IC, Peterson A, Cortes J (2018) Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol 36(9):884–890. https://doi.org/10.1200/JCO.2016.71.3495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bardia A, Dacosta NA, Gabrail NY, Lemon S, Danso MA, Ali HY et al (2016) Phase (Ph) 1 study of oral seviteronel (VT-464), a dual CYP17-lyase (L) inhibitor and androgen receptor (AR) antagonist, in patients (pts) with advanced. J Clin Oncol 34(15):1088, Ar.+ triple-negative (TNBC) or estrogen receptor (ER)+ breast cancer (BC)

  10. Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, Moses HL, Sanders ME, Pietenpol JA (2016) Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS ONE 11(6):e0157368. https://doi.org/10.1371/journal.pone.0157368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ogony JW, Radisky DC, Ruddy KJ, Goodison S, Wickland DP, Egan KM et al (2020) Immune responses and risk of triple-negative breast cancer: implications for higher rates among African American women. Cancer Prev Res 13(11):901–910

    Article  CAS  Google Scholar 

  12. Liu D, He J, Yuan Z, Wang S, Peng R, Shi Y, Teng X, Qin T (2012) EGFR expression correlates with decreased disease-free survival in triple-negative breast cancer: a retrospective analysis based on a tissue microarray. Med Oncol 29(2):401–405. https://doi.org/10.1007/s12032-011-9827-x

    Article  CAS  PubMed  Google Scholar 

  13. Vera-Badillo FE, Chang MC, Kuruzar G, Ocana A, Templeton AJ, Seruga B, Goldstein R, Bedard PL, Tannock IF, Amir E (2015) Association between androgen receptor expression, Ki-67 and the 21-gene recurrence score in non-metastatic, lymph node-negative, estrogen receptor-positive and HER2-negative breast cancer. J Clin Pathol 68(10):839–843. https://doi.org/10.1136/jclinpath-2015-203012

    Article  CAS  PubMed  Google Scholar 

  14. Castiel A, Visochek L, Mittelman L, Dantzer F, Izraeli S, Cohen-Armon M (2011) Phenanthrene-derived PARP inhibitor is an extra-centrosomes de-clustering agent exclusively eradicating human cancer cells. BMC Cancer 11:412. https://doi.org/10.1186/1471-2407-11-412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xiu J, Obeid E, Gatalica Z, Reddy S, Goldstein L, Link J et al (2016) Biomarker comparison between androgen receptor—positive-triple-negative breast cancer (AR+ TNBC) and quadruple-negative breast cancer (QNBC). Cancer Res [Journal, 76](4 Supplement):P3-07-26, abstract P3-07-26

  16. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J et al (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21(13):2000–2008

    Article  CAS  PubMed  Google Scholar 

  17. Shi Y, Yang F, Sun Z, Zhang W, Gu J, Guan X (2017) Differential microRNA expression is associated with androgen receptor expression in breast cancer. Mol Med Rep 15(1):29–36. https://doi.org/10.3892/mmr.2016.6019

    Article  CAS  PubMed  Google Scholar 

  18. Bhattarai S, Saini G, Gogineni K, Aneja R (2020) Quadruple-negative breast cancer: novel implications for a new disease. Breast Cancer Res 22(1):1–11

    Article  Google Scholar 

  19. Naorem LD, Muthaiyan M, Venkatesan A (2019) Integrated network analysis and machine learning approach for the identification of key genes of triple-negative breast cancer. J Cell Biochem 120(4):6154–6167. https://doi.org/10.1002/jcb.27903

    Article  CAS  PubMed  Google Scholar 

  20. Nakai K, Hung MC, Yamaguchi H (2016) A perspective on anti-EGFR therapies targeting triple-negative breast cancer. Am J Cancer Res 6(8):1609

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Nakagawa M, Bando Y, Nagao T, Takai C, Ohnishi T, Honda J et al (2012) Among triple-negative breast cancers, HER2 (0) breast cancer shows a strong tendency to be basal-like compared with HER2 (1+) breast cancer: preliminary results. Breast Cancer 19:54–59

    Article  PubMed  Google Scholar 

  22. Curigliano G, Pivot X, Cortés J, Elias A, Cesari R, Khosravan R, Collier M, Huang X, Cataruozolo PE, Kern KA, Goldhirsch A (2013) Randomized phase II study of sunitinib versus standard of care for patients with previously treated advanced triple-negative breast cancer. Breast 22(5):650–656. https://doi.org/10.1016/j.breast.2013.07.037

    Article  PubMed  Google Scholar 

  23. Soria JC, DeBraud F, Bahleda R, Adamo B, Andre F, Dientsmann R, Delmonte A, Cereda R, Isaacson J, Litten J, Allen A, Dubois F, Saba C, Robert R, D’Incalci M, Zucchetti M, Camboni MG, Tabernero J (2014) Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of Lusitania in advanced solid tumors. Ann Oncol 25(11):2244–2251. https://doi.org/10.1093/annonc/mdu390

    Article  PubMed  Google Scholar 

  24. Tolaney SM, Ziehr DR, Guo H, Ng MR, Barry WT, Higgins MJ, Isakoff SJ, Brock JE, Ivanova EV, Paweletz CP, Demeo MK, Ramaiya NH, Overmoyer BA, Jain RK, Winer EP, Duda DG (2017) Phase II and biomarker study of cabozantinib in metastatic triple-negative breast cancer patients. Oncologist 22(1):25–32. https://doi.org/10.1634/theoncologist.2016-0229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Abbaspour Babaei M, Kamalidehghan B, Saleem M, Huri HZ, Ahmadipour F (2016) Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells. Drug Des Dev Ther 10:2443–2459. https://doi.org/10.2147/DDDT.S89114

    Article  Google Scholar 

  26. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  27. Hu Y, Gao J, Wang M, Li M (2021) Potential prospect of CDK4/6 inhibitors in triple-negative breast cancer. Cancer Manag Res 13:5223–5237. https://doi.org/10.2147/CMAR.S310649

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bailey CM, Liu Y, Peng G, Zhang H, He M, Sun D, Zheng P, Liu Y, Wang Y (2020) Liposomal formulation of HIF-1α inhibitor echinomycin eliminates established metastases of triple-negative breast cancer. Nanomedicine 29:102278. https://doi.org/10.1016/j.nano.2020.102278

    Article  CAS  PubMed  Google Scholar 

  29. McDonald PC, Chafe SC, Dedhar S (2016) Overcoming hypoxia-mediated tumor progression: combinatorial approaches targeting pH regulation, angiogenesis and immune dysfunction. Front Cell Dev Biol 4:27

    Article  PubMed  PubMed Central  Google Scholar 

  30. Mboge MY, Combs J, Singh S, Andring J, Wolff A, Tu C et al (2021) Inhibition of carbonic anhydrase using SLC-149: support for a noncatalytic function of CAIX in breast cancer. J Med Chem 64(3):1713–1724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rajput K, Ansari MN, Jha SK, Pani T, Medatwal N, Chattopadhyay S et al (2022) Ceramide kinase (CERK) emerges as a common therapeutic target for triple positive and triple negative breast cancer cells. Cancers 14(18):4496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Haritha NH, Nawab A, Vijayakurup V, Anto NP, Liju VB, Alex VV, Amrutha AN, Aiswarya SU, Swetha M, Vinod BS, Sundaram S, Guijarro MV, Herlevich T, Krishna A, Nestory NK, Bava SV, Sadasivan C, Zajac-Kaye M, Anto RJ (2021) Targeting thymidylate synthase enhances the chemosensitivity of triple-negative breast cancer towards 5-FU-based combinatorial therapy. Front Oncol 11:656804. https://doi.org/10.3389/fonc.2021.656804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pascual-Vargas P, Cooper S, Sero J et al (2017) RNAi screens for Rho GTPase regulators of cell shape and YAP/TAZ localisation in triple negative breast cancer. Sci Data 4:170018. https://doi.org/10.1038/sdata.2017.18

    Article  PubMed  PubMed Central  Google Scholar 

  34. Wu X, Li Y, Wang J, Wen X, Marcus MT, Daniels G et al (2013) Long chain fatty acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer. PLoS ONE 8(10):e77060

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  35. Duhoux FP, Jager A, Dirix L, Huizing MT, Jerusalem GHM, Vuylsteke P, De Cuypere E, Breiner D, Mueller C, Brignone C, Triebel F (2017) Combination of paclitaxel and LAG3-Ig (IMP321), a novel MHC class II agonist, as a first-line chemoimmunotherapy in patients with metastatic breast carcinoma (MBC): interim results from the run-in phase of a placebo-controlled randomized phase II. J Clin Oncol 35(15):1062. https://doi.org/10.1200/JCO.2017.35.15_suppl.1062

    Article  Google Scholar 

  36. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L (2016) Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 34(21):2460–2467. https://doi.org/10.1200/JCO.2015.64.8931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wu L, Grigoryan AV, Li Y, Hao B, Pagano M, Cardozo TJ (2012) Specific small molecule inhibitors of Skp2-mediated p27 degradation. Chem Biol 19(12):1515–1524. https://doi.org/10.1016/j.chembiol.2012.09.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dannenmann SR, Thielicke J, Stöckli M, Matter C, von Boehmer L, Cecconi V, Hermanns T, Hefermehl L, Schraml P, Moch H, Knuth A, van den Broek M (2013) Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma. Oncoimmunology 2(3):e23562. https://doi.org/10.4161/onci.23562

    Article  PubMed  PubMed Central  Google Scholar 

  39. Fang WB, Yao M, Brummer G, Acevedo D, Alhakamy N, Berkland C, Cheng N (2016) Targeted gene silencing of CCL2 inhibits triple-negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment. Oncotarget 7(31):49349–49367. https://doi.org/10.18632/oncotarget.9885

    Article  PubMed  PubMed Central  Google Scholar 

  40. Koni M, Castellano I, Venturelli E, Sarcinella A, Lopatina T, Grange C et al (2022) Interleukin-3-receptor-α in triple-negative breast cancer (TNBC): an additional novel biomarker of TNBC aggressiveness and a therapeutic target. Cancers 14(16):3918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Takai K, Le A, Weaver VM, Werb Z (2016) Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget 7(50):82889–82901. https://doi.org/10.18632/oncotarget.12658

    Article  PubMed  PubMed Central  Google Scholar 

  42. Ström CE, Johansson F, Uhlén M, Szigyarto CA, Erixon K, Helleday T (2011) Poly(ADP-ribose) polymerase (PARP) is not involved in base excision repair but PARP inhibition traps a single-strand intermediate. Nucleic Acids Res 39(8):3166–3175. https://doi.org/10.1093/nar/gkq1241

    Article  CAS  PubMed  Google Scholar 

  43. Mourelatos Z, Dostie J, Paushkin S, Sharma A, Charroux B, Abel L, Rappsilber J, Mann M, Dreyfuss G (2002) miRNAs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev 16(6):720–728. https://doi.org/10.1101/gad.974702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Passon N, Gerometta A, Puppin C, Lavarone E, Puglisi F, Tell G et al (2012) Expression of Dicer and Drosha in triple-negative breast cancer. J Clin Pathol 65(4):320–326

    Article  CAS  PubMed  Google Scholar 

  45. Vajen B, Bhowmick R, Greiwe L, Schäffer V, Eilers M, Reinkens T et al (2022) MicroRNA-449a inhibits triple negative breast cancer by disturbing DNA repair and chromatid separation. Int J Mol Sci 23(9):5131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Darbeheshti F, Kadkhoda S, Keshavarz-Fathi M, Razi S, Bahramy A, Mansoori Y, Rezaei N (2022) Investigation of BRCAness associated miRNA-gene axes in breast cancer: cell-free miR-182-5p as a potential expression signature of BRCAness. BMC Cancer 22(1):1–13

    Article  Google Scholar 

  47. Shuaib M, Prajapati KS, Singh AK, Kushwaha PP, Waseem M, Kumar S (2022) Identification of miRNAs and related hub genes associated with the triple negative breast cancer using integrated bioinformatics analysis and in vitro approach. J Biomol Struct Dyn 40(22):11676–11690

    Article  CAS  PubMed  Google Scholar 

  48. Prvanović M, Nedeljković M, Tanić N, Tomić T, Terzić T, Milovanović Z, Maksimović Z, Tanić N (2021) Role of PTEN, PI3K, and mTOR in triple-negative breast cancer. Life (Basel, Switzerland) 11(11):1247. https://doi.org/10.3390/life11111247

    Article  CAS  PubMed  ADS  Google Scholar 

  49. Kittle H, Tschandl P (2018) Driver mutations in the mitogen-activated protein kinase pathway: the seeds of good and evil. Br J Dermatol 178(1):26–27. https://doi.org/10.1111/bjd.16119

    Article  Google Scholar 

  50. An X, Xu F, Luo R, Zheng Q, Lu J, Yang Y et al (2018) The prognostic significance of topoisomerase II alpha protein in early stage luminal breast cancer. BMC Cancer 18(1):1–10

    Article  CAS  Google Scholar 

  51. Hollern DP, Swiatnicki MR, Rennhack JP, Misek SA, Matson BC, McAuliff A, Gallo KA, Caron KM, Andrechek ER (2019) E2F1 drives breast cancer metastasis by regulating the target gene FGF13 and altering cell migration. Sci Rep 9(1):10718. https://doi.org/10.1038/s41598-019-47218-0

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  52. Engelmann D, Mayoli-Nüssle D, Mayrhofer C, Fürst K, Alla V, Stoll A, Spitschak A, Abshagen K, Vollmar B, Ran S, Pützer BM (2013) E2F1 promotes angiogenesis through the VEGF-C/VEGFR-3 axis in a feedback loop for cooperative induction of PDGF-B. J Mol Cell Biol 5(6):391–403. https://doi.org/10.1093/jmcb/mjt035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jansson S, Bendahl PO, Grabau DA, Falck AK, Fernö M, Aaltonen K, Ryden L (2014) The three receptor tyrosine kinases c-KIT, VEGFR2 and PDGFRα, closely spaced at 4q12, show increased protein expression in triple-negative breast cancer. PLoS ONE 9(7):e102176

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  54. Finn RS, Bengala C, Ibrahim N, Roché H, Sparano J, Strauss LC, Fairchild J, Sy O, Goldstein LJ (2011) Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res 17(21):6905–6913. https://doi.org/10.1158/1078-0432.CCR-11-0288

    Article  CAS  PubMed  Google Scholar 

  55. Horiuchi D, Kusdra L, Huskey NE, Chandriani S, Lenburg ME, Gonzalez-Angulo AM et al (2012) MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. J Exp Med 209(4):679–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404

    Article  PubMed  Google Scholar 

  57. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1

    Article  PubMed  PubMed Central  Google Scholar 

  58. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ et al (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pereira B, Chin SF, Rueda OM, Vollan HKM, Provenzano E, Bardwell HA et al (2016) The somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes. Nat Commun 7(1):11479

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  60. Mazumdar A, Tahaney WM, Reddy Bollu L, Poage G, Hill J, Zhang Y et al (2019) The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression. NPJ Breast Cancer 5(1):22

    Article  PubMed  PubMed Central  Google Scholar 

  61. Apostolidi M, Vathiotis IA, Muthusamy V, Gaule P, Gassaway BM, Rimm DL, Rinehart J (2021) Targeting pyruvate kinase M2 phosphorylation reverses aggressive cancer phenotypes PKM2 phosphorylation as a target for treatment of TNBC. Cancer Res 81(16):4346–4359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Soni S, Padwad YS (2017) HIF-1 in cancer therapy: two decade long story of a transcription factor. Acta Oncol 56(4):503–515

    Article  CAS  PubMed  Google Scholar 

  63. Noh S, Kim JY, Koo JS (2014) Metabolic differences in estrogen receptor-negative breast cancer based on androgen receptor status. Tumour Biol 35(8):8179–8192. https://doi.org/10.1007/s13277-014-2103-x

    Article  CAS  PubMed  Google Scholar 

  64. Siddiqui A, Gollavilli PN, Schwab A, Vazakidou ME, Ersan PG, Ramakrishnan M, Pluim D, Coggins S, Saatci O, Annaratone L, Hm Schellens J, Kim B, Asangani IA, Rasheed SAK, Marchiò C, Sahin O, Ceppi P (2019) Thymidylate synthase maintains the de-differentiated state of triple-negative breast cancers. Cell Death Differ 26(11):2223–2236. https://doi.org/10.1038/s41418-019-0289-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Saif MW, Makrilia N, Syrigos K (2010) Cofactor: folate requirement for optimization of 5-fluorouracil activity in anticancer chemotherapy. J Oncol 2010:934359. https://doi.org/10.1155/2010/934359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Orlando UD, Castillo AF, Dattilo MA, Solano AR, Maloberti PM, Podesta EJ (2015) Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and-negative breast cancer. Oncotarget 6(40):42632

    Article  PubMed  PubMed Central  Google Scholar 

  67. Monaco ME (2023) ACSL4: biomarker, mediator and target in quadruple negative breast cancer. Oncotarget 14:563–575. https://doi.org/10.18632/oncotarget.28453

    Article  PubMed  PubMed Central  Google Scholar 

  68. Miricescu D, Totan A, Stanescu-Spinu II, Badoiu SC, Stefani C, Greabu M (2020) PI3K/AKT/mTOR signaling pathway in breast cancer: from molecular landscape to clinical aspects. Int J Mol Sci 22(1):173

    Article  PubMed  PubMed Central  Google Scholar 

  69. Goldberg MV, Drake CG (2011) LAG-3 in cancer immunotherapy. Curr Top Microbiol Immunol 344:269–278. https://doi.org/10.1007/82_2010_114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Corti C, Nicolò E, Curigliano G (2021) Novel immune targets for the treatment of triple-negative breast cancer. Expert Opin Ther Targets 25(10):815–834

    Article  CAS  PubMed  Google Scholar 

  71. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571. https://doi.org/10.1038/nature13954

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  72. García-Teijido P, Cabal ML, Fernández IP, Pérez YF (2016) Tumor-infiltrating lymphocytes in triple-negative breast cancer: the future of immune targeting. Clin Med Insights Oncol 10(Suppl 1):31–39. https://doi.org/10.4137/CMO.S34540

    Article  PubMed  PubMed Central  Google Scholar 

  73. Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, Su XP, Wang Y, Gonzalez-Angulo AM, Akcakanat A, Chawla A, Curran M, Hwu P, Sharma P, Litton JK, Molldrem JJ, Alatrash G (2014) PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2(4):361–370. https://doi.org/10.1158/2326-6066.CIR-13-0127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Li CW, Lim SO, Chung EM, Kim YS, Park AH, Yao J, Cha JH, Xia W, Chan LC, Kim T et al (2018) Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1. Cancer Cell 33(2):(187-201.e10):e110. https://doi.org/10.1016/j.ccell.2018.01.009

    Article  CAS  Google Scholar 

  75. Brockwell NK, Owen KL, Zanker D, Spurling A, Rautela J, Duivenvoorden HM, Baschuk N, Caramia F, Loi S, Darcy PK, Lim E, Parker BS (2017) Neoadjuvant interferons: critical for effective PD-1-based immunotherapy in TNBC. Cancer Immunol Res 5(10):871–884. https://doi.org/10.1158/2326-6066.CIR-17-0150

    Article  CAS  PubMed  Google Scholar 

  76. Li X, Tang L, Chen Q, Cheng X, Liu Y, Wang C et al (2022) Inhibition of MYC suppresses programmed cell death ligand-1 expression and enhances immunotherapy in triple-negative breast cancer. Chin Med J 135(20):2436–2445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang Z, Fukushima H, Inuzuka H, Wan L, Liu P, Gao D, Sarkar FH, Wei W (2012) Skp2 is a promising therapeutic target in breast cancer. Front Oncol 1(57):57. https://doi.org/10.3389/fonc.2011.00057

    Article  PubMed  PubMed Central  Google Scholar 

  78. Li B, Lu W, Yang Q, Yu X, Matusik RJ, Chen Z (2014) Skp2 regulates androgen receptors through ubiquitin-mediated degradation independent of Akt/mTOR pathways in prostate cancer. Prostate 74(4):421–432. https://doi.org/10.1002/pros.22763

    Article  CAS  PubMed  Google Scholar 

  79. Signoretti S, Di Marcotullio L, Richardson A, Ramaswamy S, Isaac B, Rue M, Monti F, Loda M, Pagano M (2002) Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. J Clin Investig 110(5):633–641. https://doi.org/10.1172/JCI0215795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. O’Hayre M, Salanga CL, Handel TM, Allen SJ (2008) Chemokines and cancer: migration, intracellular signaling, and intercellular communication in the microenvironment. Biochem J 409(3):635–649. https://doi.org/10.1042/BJ20071493

    Article  CAS  PubMed  Google Scholar 

  81. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumor-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14(7):399–416. https://doi.org/10.1038/nrclinonc.2016.217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Dougan M, Dranoff G, Dougan SK (2019) GM-CSF, IL-3, and IL-5 family of cytokines: regulators of inflammation. Immunity 50(4):796–811

    Article  CAS  PubMed  Google Scholar 

  83. Marra A, Trapani D, Viale G, Criscitiello C, Curigliano G (2020) Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies. npj breast cancer 6(1):54

    Article  PubMed  PubMed Central  Google Scholar 

  84. Khan KA, Kerbel RS (2018) Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 15(5):310–324

    Article  CAS  PubMed  Google Scholar 

  85. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT (2010) Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330(6005):827–830. https://doi.org/10.1126/science.1195300

    Article  CAS  PubMed  ADS  Google Scholar 

  86. Verona EV, Elkahloun AG, Yang J, Bandyopadhyay A, Yeh IT, Sun LZ (2007) Transforming growth factor-beta signaling in prostate stromal cells supports prostate carcinoma growth by upregulating stromal genes related to tissue remodeling. Cancer Res 67(12):5737–5746. https://doi.org/10.1158/0008-5472.CAN-07-0444

    Article  CAS  PubMed  Google Scholar 

  87. Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, Altman RB (2011) Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics 21(7):440–446. https://doi.org/10.1097/FPC.0b013e32833ffb56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bhola NE, Balko JM, Dugger TC, Kuba MG, Sánchez V, Sanders M, Stanford J, Cook RS, Arteaga CL (2013) TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Investig 123(3):1348–1358. https://doi.org/10.1172/JCI65416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, Almeida D, Koller A, Hajjar KA, Stainier DY, Chen EI, Lyden D, Bissell MJ (2013) The perivascular niche regulates breast tumor dormancy. Nat Cell Biol 15(7):807–817. https://doi.org/10.1038/ncb2767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rizwan A, Bulte C, Kalaichelvan A, Cheng M, Krishnamachary B, Bhujwalla ZM, Jiang L, Glunde K (2015) Metastatic breast cancer cells in lymph nodes increase nodal collagen density. Sci Rep 5:10002. https://doi.org/10.1038/srep10002

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  91. Papadimitriou M, Mountzios G, Papadimitriou CA (2018) The role of PARP inhibition in triple-negative breast cancer: unraveling the wide spectrum of synthetic lethality. Cancer Treat Rev 67:34–44

    Article  CAS  PubMed  Google Scholar 

  92. Luo L, Keyomarsi K (2022) PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers. Expert Opin Investig Drugs 31(6):607–631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jiang X, Li X, Li W, Bai H, Zhang Z (2019) PARP inhibitors in ovarian cancer: sensitivity prediction and resistance mechanisms. J Cell Mol Med 23(4):2303–2313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mateo J, Lord CJ, Serra V, Tutt A, Balmaña J, Castroviejo-Bermejo M et al (2019) A decade of clinical development of PARP inhibitors in perspective. Ann Oncol 30(9):1437–1447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Xia M, Zu X, Chen Z, Wen G, Zhong J (2021) Noncoding RNAs in triple negative breast cancer: mechanisms for chemoresistance. Cancer Lett 523:100–110

    Article  CAS  PubMed  Google Scholar 

  96. Volinia S, Galasso M, Sana ME, Wise TF, Palatini J, Huebner K, Croce CM (2012) Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA. Proc Natl Acad Sci USA 109(8):3024–3029

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  97. Cascione L, Gasparini P, Lovat F, Carasi S, Pulvirenti A, Ferro A et al (2013) Integrated microRNA and mRNA signatures associated with survival in triple negative breast cancer. PLoS ONE 8(2):e55910

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  98. Paszek S, Gabło N, Barnaś E, Szybka M, Morawiec J, Kołacińska A, Zawlik I (2017) Dysregulation of microRNAs in triple-negative breast cancer. Ginekol Pol 88(10):530–536

    Article  PubMed  Google Scholar 

  99. Kim Y, Ko JY, Lee SB, Oh S, Park JW, Kang HG et al (2022) Reduced miR-371b-5p expression drives tumor progression via CSDE1/RAC1 regulation in triple-negative breast cancer. Oncogene 41(22):3151–3161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Paul U, Banerjee S (2022) The functional significance and cross-talk of non-coding RNAs in triple negative and quadruple negative breast cancer. Mol Biol Rep. https://doi.org/10.1007/s11033-022-07288-2

    Article  PubMed  Google Scholar 

  101. Cheng YT, Nakagawa-Goto K, Lee KH, Shyur LF (2023) MicroRNA-mediated mitochondrial dysfunction is involved in the anti-triple-negative breast cancer cell activity of phytosesquiterpene lactones. Antioxid Redox Signal 38(1–3):198–214

    Article  CAS  PubMed  Google Scholar 

  102. Mellor P, Deibert L, Calvert B, Bonham K, Carlsen SA, Anderson DH (2013) CREB3L1 is a metastasis suppressor that represses expression of genes regulating metastasis, invasion, and angiogenesis. Mol Cell Biol 33(24):4985–4995. https://doi.org/10.1128/MCB.00959-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcomes. Cell Stem Cell 1(5):555–567. https://doi.org/10.1016/j.stem.2007.08.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988. https://doi.org/10.1073/pnas.0530291100

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  105. Liu H, Patel MR, Prescher JA, Patsialou A, Qian D, Lin J, Wen S, Chang YF, Bachmann MH, Shimono Y, Dalerba P, Adorno M, Lobo N, Bueno J, Dirbas FM, Goswami S, Somlo G, Condeelis J, Contag CH et al (2010) Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci USA 107(42):18115–18120. https://doi.org/10.1073/pnas.1006732107

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  106. Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, Martin-Trevino R, Shang L, McDermott SP, Landis MD, Hong S, Adams A, D’Angelo R, Ginestier C, Charafe-Jauffret E, Clouthier SG, Birnbaum D, Wong ST, Zhan M et al (2014) Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep 2(1):78–91. https://doi.org/10.1016/j.stemcr.2013.11.009

    Article  CAS  Google Scholar 

  107. Ohi Y, Umekita Y, Yoshioka T, Souda M, Rai Y, Sagara Y, Sagara Y, Sagara Y, Tanimoto A (2011) Aldehyde dehydrogenase 1 expression predicts poor prognosis in triple-negative breast cancer. Histopathology 59(4):776–780. https://doi.org/10.1111/j.1365-2559.2011.03884.x

    Article  PubMed  Google Scholar 

  108. Opyrchal M, Salisbury JL, Iankov I, Goetz MP, McCubrey J, Gambino MW, Malatino L, Puccia G, Ingle JN, Galanis E, D’Assoro AB (2014) Inhibition of CDK2 kinase activity selectively targets the CD44+/CD24−/low stem-like subpopulation and restores chemosensitivity of SUM149PT triple-negative breast cancer cells. Int J Oncol 45(3):1193–1199. https://doi.org/10.3892/ijo.2014.2523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Man SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715. https://doi.org/10.1016/j.cell.2008.03.027

    Article  CAS  Google Scholar 

  110. Wu Q, Wang J, Liu Y, Gong X (2019) Epithelial cell adhesion molecule and epithelial-mesenchymal transition are associated with vasculogenic mimicry, poor prognosis, and metastasis of triple-negative breast cancer. Int J Clin Exp Pathol 12(5):1678–1689

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, D’Alessio AC, Young RA, Weinberg RA (2013) Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154:61–74. https://doi.org/10.1016/j.cell.2013.06.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ki SY, Kang JW, Song X, Kim BK, Yoo YD, Kwon YT, Lee YJ (2013) Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. Cell Signal 25(4):961–969. https://doi.org/10.1016/j.cellsig.2013.01.007

    Article  CAS  Google Scholar 

  113. O’Shaughness J, DeMichele A, Ma CX, Richards P, Yardley DA, Wright GS, Kalinsky K, Steis R, Diab S, Kennealey G, Geschwindt R, Jiang W, Rugo HS (2018) A randomized, double-blind, phase 2 study of ruxolitinib or placebo in combination with capecitabine in patients with advanced HER2-negative breast cancer and elevated C-reactive protein, a marker of systemic inflammation. Breast Cancer Res Treat 170(3):547–557. https://doi.org/10.1007/s10549-018-4770-6

    Article  CAS  Google Scholar 

  114. Stover DG, Gil Del Alcazar CR, Brock J, Guo H, Overmoyer B, Balko J, Xu Q, Bardia A, Tolaney SM, Gelman R, Lloyd M, Wang Y, Xu Y, Michor F, Wang V, Winer EP, Polyak K, Lin NU (2018) Phase II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer. npj Breast Cancer 4:10. https://doi.org/10.1038/s41523-018-0060-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tian J, Raffa FA, Dai M, Moamer A, Khadang B, Hachim IY, Bakdounes K, Ali S, Jean-Claude B, Lebrun JJ (2018) Dasatinib sensitizes triple-negative breast cancer cells to chemotherapy by targeting breast cancer stem cells. Br J Cancer 119(12):1495–1507. https://doi.org/10.1038/s41416-018-0287-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sato, K., Padgaonkar, A. A., Baker, S. J., Cosenza, S. C., Rechkoblit, O., Subbaiah, D. V., ... & Reddy, E. P. (2021). Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease. Nature communications, 12(1), 4671.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  117. Fernández-Martínez P, Zahonero C, Sánchez-Gómez P (2015) DYRK1A: the double-edged kinase as a protagonist in cell growth and tumorigenesis. Mol Cell Oncol 2(1):e970048. https://doi.org/10.4161/23723548.2014.970048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Gao J, Zheng Z, Rawal B, Schell MJ, Bepler G, Haura EB (2009) Mirk/Dyrk1B, a novel therapeutic target, mediates cell survival in non-small cell lung cancer cells. Cancer Biol Ther 8(17):1671–1679. https://doi.org/10.4161/cbt.8.17.9322

    Article  CAS  PubMed  Google Scholar 

  119. Song DH, Dominguez I, Mizuno J, Kaut M, Mohr SC, Seldin DC (2003) CK2 phosphorylation of the armadillo repeat region of beta-catenin potentiates Wnt signaling. J Biol Chem 278(26):24018–24025. https://doi.org/10.1074/jbc.M212260200

    Article  CAS  PubMed  Google Scholar 

  120. Tapia JC, Torres VA, Rodriguez DA, Leyton L, Quest AF (2006) Casein kinase 2 (CK2) increases surviving expression via enhanced beta-catenin-T cell factor/lymphoid enhancer-binding factor-dependent transcription. Proc Natl Acad Sci USA 103(41):15079–15084. https://doi.org/10.1073/pnas.0606845103

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  121. Wang S, Jones KA (2006) CK2 controls the recruitment of Wnt regulators to target genes in vivo. Curr Biol 16(22):2239–2244. https://doi.org/10.1016/j.cub.2006.09.034

    Article  CAS  PubMed  Google Scholar 

  122. Di Maira G, Salvi M, Arrigoni G, Marin O, Sarno S, Brustolon F, Pinna LA, Ruzzene M (2005) Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ 12(6):668–677. https://doi.org/10.1038/sj.cdd.4401604

    Article  CAS  PubMed  Google Scholar 

  123. Zhang S, Wang Y, Mao JH, Hsieh D, Kim IJ, Hu LM, Xu Z, Long H, Jablons DM, You L (2012) Inhibition of CK2alpha down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human lung cancer cells. PLoS ONE 7(6):e38996. https://doi.org/10.1371/journal.pone.0038996

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  124. Zhang S, Yang YL, Wang Y, You B, Dai Y, Chan G, Hsieh D, Kim IJ, Fang LT, Au A, Stoppler HJ, Xu Z, Jablons DM, You L (2014) CK2 alpha, over-expressed in human malignant pleural mesothelioma, regulates the Hedgehog signaling pathway in mesothelioma cells. J Exp Clin Cancer Res 33:93. https://doi.org/10.1186/s13046-014-0093-6

    Article  PubMed  PubMed Central  Google Scholar 

  125. Zhang S, Long H, Yang YL, Wang Y, Hsieh D, Li W, Au A, Stoppler HJ, Xu Z, Jablons DM, You L (2013) Inhibition of CK2alpha down-regulates Notch1 signaling in lung cancer cells. J Cell Mol Med 17(7):854–862. https://doi.org/10.1111/jcmm.12068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Nalla LV, Kalia K, Khairnar A (2019) Self-renewal signaling pathways in breast cancer stem cells. Int J Biochem Cell Biol 107:140–153. https://doi.org/10.1016/j.biocel.2018.12.017

    Article  CAS  PubMed  Google Scholar 

  127. Shibue T, Weinberg RA (2017) EMT, CSCS, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14(10):611–629. https://doi.org/10.1038/nrclinonc.2017.44

    Article  PubMed  PubMed Central  Google Scholar 

  128. Bian Y, Ye M, Wang C, Cheng K, Song C, Dong M, Pan Y, Qin H, Zou H (2013) Global screening of CK2 kinase substrates by an integrated phosphoproteomics workflow. Sci Rep 3:3460. https://doi.org/10.1038/srep03460

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  129. Gyenis L, Litchfield DW (2008) The emerging CK2 interactome: insights into the regulation and functions of CK2. Mol Cell Biochem 316(1–2):5–14. https://doi.org/10.1007/s11010-008-9830-5

    Article  CAS  PubMed  Google Scholar 

  130. Rusin SF, Adamo ME, Kettenbach AN (2017) Identification of candidate casein kinase 2 substrates in mitosis by quantitative phosphoproteomics. Front Cell Dev Biol 5:97. https://doi.org/10.3389/fcell.2017.00097

    Article  PubMed  PubMed Central  Google Scholar 

  131. Rowse AL, Gibson SA, Meares GP, Rajbhandari R, Nozell SE, Dees KJ, Hjelmeland AB, McFarland BC, Benveniste EN (2017) Protein kinase CK2 is important for the function of glioblastoma brain tumor-initiating cells. J Neuro-Oncol 132(2):219–229. https://doi.org/10.1007/s11060-017-2378-z

    Article  CAS  Google Scholar 

  132. So KS, Rho JK, Choi YJ, Kim SY, Choi CM, Chun YJ, Lee JC (2015) AKT/mTOR down-regulation by CX-4945, a CK2 inhibitor, promotes apoptosis in chemorefractory non-small cell lung cancer cells. Anticancer Res 35(3):1537–1542

    CAS  PubMed  Google Scholar 

  133. Takahashi K, Setoguchi T, Tsuru A, Saitoh Y, Nagano S, Ishidou Y, Maeda S, Furukawa T, Komiya S (2017) Inhibition of casein kinase 2 prevents the growth of human osteosarcoma. Oncol Rep 37(2):1141–1147. https://doi.org/10.3892/or.2016.5310

    Article  CAS  PubMed  Google Scholar 

  134. Banstola A, Poudel K, Emami F, Ku SK, Jeong JH, Kim JO, Yook S (2021) Localized therapy using anti-PD-L1 anchored and NIR-responsive hollow gold nanoshell (HGNS) loaded with doxorubicin (DOX) for the treatment of locally advanced melanoma. Nanomedicine 33:102349. https://doi.org/10.1016/j.nano.2020.102349

    Article  CAS  PubMed  Google Scholar 

  135. Kalyani D, Raval N, Maheshwari R, Tambe V, Kalia K, Takada RK (2019) Employment of the enhanced permeability and retention effect (EPR): nanoparticle-based precision tools for targeting the therapeutic and diagnostic agent in cancer. Mater Sci Eng C 98:1252–1276

    Article  Google Scholar 

  136. Chen WL, Yang SD, Li F, Qu CX, Liu Y, Wang Y, Wang DD, Zhang XN (2018) Programmed pH/reduction-responsive nanoparticles for efficient delivery of antitumor agents in vivo. Acta Biomater 81:219–230. https://doi.org/10.1016/j.actbio.2018.09.040

    Article  CAS  PubMed  Google Scholar 

  137. Du J, Lane LA, Nie S (2015) Stimuli-responsive nanoparticles for targeting the tumor microenvironment. J Control Release 219:205–214. https://doi.org/10.1016/j.jconrel.2015.08.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Son S, Shin S, Rao NV, Um W, Jeon J, Ko H, Deepagan VG, Kwon S, Lee JY, Park JH (2018) Anti-Trop2 antibody-conjugated reducible nanoparticles for targeted triple-negative breast cancer therapy. Int J Biol Macromol 110:406–415. https://doi.org/10.1016/j.ijbiomac.2017.10.113

    Article  CAS  PubMed  Google Scholar 

  139. Hossen S, Hossain MK, Basher MK, Mia MNH, Rahman MT, Uddin MJ (2019) Smart nano carrier-based drug delivery systems for cancer therapy and toxicity studies: a review. J Adv Res 15:1–18. https://doi.org/10.1016/j.jare.2018.06.005

    Article  CAS  PubMed  Google Scholar 

  140. Yazdi SJM, Cho KS, Kang N (2018) Characterization of the viscoelastic model of in vivo human posterior thigh skin using ramp-relaxation indentation test. Korea-Aust Rheol J 30(4):293–307. https://doi.org/10.1007/s13367-018-0027-5

    Article  Google Scholar 

  141. Xu C, Yu Y, Sun Y, Kong L, Yang C, Hu M, Yang T, Zhang J, Hu Q, Zhang Z (2019) Transformable nanoparticle-enabled synergistic elicitation and promotion of immunogenic cell death for triple-negative breast cancer immunotherapy. Adv Funct Mater. https://doi.org/10.1002/adfm.201905213

    Article  PubMed  PubMed Central  Google Scholar 

  142. Shashni B, Nagasaki YJB (2018) Nitroxide radical-containing nanoparticles attenuate the tumorigenic potential of triple-negative breast cancer. Biomaterials 178:48–62. https://doi.org/10.1016/j.biomaterials.2018.05.042

    Article  CAS  PubMed  Google Scholar 

  143. Fan Y, Wang Q, Lin G, Shi Y, Gu Z, Ding T (2017) Combination of using prodrug-modified cationic liposome nanocomplexes and a potentiating strategy via targeted co-delivery of gemcitabine and docetaxel for CD44-overexpressed triple-negative breast cancer therapy. Acta Biomater 62:257–272. https://doi.org/10.1016/j.actbio.2017.08.034

    Article  CAS  PubMed  Google Scholar 

  144. Hu G, Chun X, Wang Y, He Q, Gao H (2015) Peptide-mediated active targeting and intelligent particle size reduction-mediated enhanced penetrating of fabricated nanoparticles for triple-negative breast cancer treatment. Oncotarget 6(38):41258–41274. https://doi.org/10.18632/oncotarget.5692

    Article  PubMed  PubMed Central  Google Scholar 

  145. Guha, L., Bhat, I. A., Bashir, A., Rahman, J. U., & Pottoo, F. H. (2022). Nanotechnological Approaches for the Treatment of Triple-Negative Breast Cancer: A Comprehensive Review. Curr Drug Metab 23(10):781–799

  146. Alimoradi H, Greish K, Barzegar-Fallah A, Alshaibani L, Pittalà V (2018) Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity. Int J Nanomed 13:7771–7787. https://doi.org/10.2147/IJN.S187089

    Article  CAS  Google Scholar 

  147. Wang Y, Xie Y, Li J, Peng ZH, Sheinin Y, Zhou J, Oupický D (2017) Tumor-penetrating nanoparticles for enhanced anticancer activity of combined photodynamic and hypoxia-activated therapy. ACS Nano 11(2):2227–2238. https://doi.org/10.1021/acsnano.6b08731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Ding Y, Su S, Zhang R, Shao L, Zhang Y, Wang B, Li Y, Chen L, Yu Q, Wu YJB, Nie G (2017) Precision combination therapy for triple-negative breast cancer via biomimetic polydopamine polymer core-shell nanostructures. Biomaterials 113:243–252. https://doi.org/10.1016/j.biomaterials.2016.10.053

    Article  CAS  PubMed  Google Scholar 

  149. Keihan Shokooh M, Emami F, Jeong JH, Yook S (2021) Bio-inspired and smart nanoparticles for triple-negative breast cancer microenvironment. Pharmaceutics 13(2):287. https://doi.org/10.3390/pharmaceutics13020287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Catalano A, Iacopetta D, Pellegrino M, Aquaro S, Franchini C, Sinicropi MS (2021) Diarylureas: repositioning from antitumor to antimicrobials or multi-target agents against new pandemics. Antibiotics 2021(10):92

    Article  Google Scholar 

  151. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A et al (2019) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18(1):41–58

    Article  CAS  PubMed  Google Scholar 

  152. Talarico G, Orecchioni S, Dallaglio K, Reggiani F, Mancuso P, Calleri A et al (2016) Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells. Sci Rep 6(1):18673

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  153. Xie WY, He RH, Zhang J, He YJ, Wan Z, Zhou CF et al (2019) βblockers inhibit the viability of breast cancer cells by regulating the ERK/COX2 signaling pathway and the drug response is affected by ADRB2 singlenucleotide polymorphisms. Oncol Rep 41(1):341–350

    CAS  PubMed  Google Scholar 

  154. Xie W, Zhang Y, Zhang S, Wang F, Zhang K, Huang Y et al (2019) Oxymatrine enhanced anti-tumor effects of bevacizumab against triple-negative breast cancer via abating Wnt/β-catenin signaling pathway. Am J Cancer Res 9(8):1796

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Gucalp A, Traina TA (2016) Targeting the androgen receptor in triple-negative breast cancer. Curr Probl Cancer 40(2–4):141–150

    Article  PubMed  PubMed Central  Google Scholar 

  156. Mercurio A, Adriani G, Catalano A, Carocci A, Rao L, Lentini G et al (2017) A mini-review on thalidomide: chemistry, mechanisms of action, therapeutic potential and anti-angiogenic properties in multiple myeloma. Curr Med Chem 24(25):2736–2744

    Article  CAS  PubMed  Google Scholar 

  157. Iacopetta D, Carocci A, Sinicropi MS, Catalano A, Lentini G, Ceramella J et al (2017) Old drug scaffold, new activity: thalidomide-correlated compounds exert different effects on breast cancer cell growth and progression. ChemMedChem 12(5):381–389

    Article  CAS  PubMed  Google Scholar 

  158. Dai X, Yin C, Zhang Y, Guo G, Zhao C, Wang O et al (2018) Osthole inhibits triple negative breast cancer cells by suppressing STAT3. J Exp Clin Cancer Res 37(1):1–11

    Article  Google Scholar 

  159. Palaka BK, Venkatesan R, Ampasala DR, Periyasamy L (2019) Identification of novel inhibitors of signal transducer and activator of transcription 3 over signal transducer and activator of transcription 1 for the treatment of breast cancer by in-silico and in-vitro approach. Process Biochem 82:153–166

    Article  Google Scholar 

  160. Oh E, Kim YJ, An H, Sung D, Cho TM, Farrand L et al (2018) Flubendazole elicits anti-metastatic effects in triple-negative breast cancer via STAT3 inhibition. Int J Cancer 143(8):1978–1993

    Article  CAS  PubMed  Google Scholar 

  161. Wang YC, Chao TK, Chang CC, Yo YT, Yu MH, Lai HC (2013) Drug screening identifies niclosamide as an inhibitor of breast cancer stem-like cells. PLoS ONE 8(9):e74538

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  162. Botteri E, Munzone E, Rotmensz N, Cipolla C, De Giorgi V, Santillo B et al (2013) Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res Treat 140:567–575

    Article  CAS  PubMed  Google Scholar 

  163. Musini VM, Pasha P, Gill R, Wright JM (2017) Blood pressure lowering efficacy of clonidine for primary hypertension. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD008284.pub3

    Article  PubMed  PubMed Central  Google Scholar 

  164. Choi DS, Blanco E, Kim YS, Rodriguez AA, Zhao H, Huang THM et al (2014) Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells 32(9):2309–2323

    Article  CAS  PubMed  Google Scholar 

  165. King TD, Suto MJ, Li Y (2012) The wnt/β-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer. J Cell Biochem 113(1):13–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Xu L, Zhang LE, Hu C, Liang S, Fei X, Yan N et al (2016) WNT pathway inhibitor pyrvinium pamoate inhibits the self-renewal and metastasis of breast cancer stem cells. Int J Oncol 48(3):1175–1186

    Article  CAS  PubMed  Google Scholar 

  167. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES (2009) Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138(4):645–659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. So JY, Suh N (2015) Targeting cancer stem cells in solid tumors by vitamin D. J Steroid Biochem Mol Biol 148:79–85

    Article  CAS  PubMed  ADS  Google Scholar 

  169. Thorne CA, Hanson AJ, Schneider J, Tahinci E, Orton D, Cselenyi CS et al (2010) Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat Chem Biol 6(11):829–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Wahler J, So JY, Cheng LC, Maehr H, Uskokovic M, Suh N (2015) Vitamin D compounds reduce mammosphere formation and decrease expression of putative stem cell markers in breast cancer. J Steroid Biochem Mol Biol 148:148–155

    Article  CAS  PubMed  Google Scholar 

  171. Dattilo R, Mottini C, Camera E, Lamolinara A, Auslander N, Doglioni G et al (2020) Pyrvinium pamoate induces death of triple-negative breast cancer stem-like cells and reduces metastases through effects on lipid anabolism. Cancer Res 80(19):4087–4102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Bhattacharya U, Kamran M, Manai M, Cristofanilli M, Ince TA (2023) Cell-of-origin targeted drug repurposing for triple-negative and inflammatory breast carcinoma with HDAC and HSP90 inhibitors combined with niclosamide. Cancers 15(2):332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Goyette MA, Cusseddu R, Elkholi I, Abu-Thuraia A, El-Hachem N, Haibe-Kains B et al (2019) AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer. Oncotarget 10(21):2055

    Article  PubMed  PubMed Central  Google Scholar 

  174. Cole SW, Sood AK (2012) Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res 18(5):1201–1206

    Article  CAS  PubMed  Google Scholar 

  175. Yin SY, Wei WC, Jian FY, Yang NS (2013) Therapeutic applications of herbal medicines for cancer patients. Evid Based Complement Altern Med 2013:302426. https://doi.org/10.1155/2013/302426

    Article  Google Scholar 

  176. Tavakoli J, Miar S, Majid Zadehzare M, Akbari H (2012) Evaluation of effectiveness of herbal medication in cancer care: a review study. Iran J Cancer Prev 5(3):144–156

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Yang Z, Zhang Q, Yu L, Zhu J, Cao Y, Gao X (2021) The signaling pathways and targets of traditional Chinese medicine and natural medicine in triple-negative breast cancer. J Ethnopharmacol 264:113249

    Article  CAS  PubMed  Google Scholar 

  178. Zhang Y, Talalay P, Cho CG, Posner GH (1992) A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci USA 89(6):2399–2403. https://doi.org/10.1073/pnas.89.6.2399

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  179. Zaveri NT (2006) Green tea and its polyphenolic catechins: medicinal uses in cancer and noncancerous applications. Life Sci 78:2073–2080

    Article  CAS  PubMed  Google Scholar 

  180. Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B et al (2010) Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells sulforaphane inhibits breast cancer stem cells. Clin Cancer Res 16(9):2580–2590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Lu W, Lin C, King TD, Chen H, Reynolds RC, Li Y (2012) Silibinin inhibits Wnt/β-catenin signaling by suppressing Wnt co-receptor LRP6 expression in human prostate and breast cancer cells. Cell Signal 24(12):2291–2296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Pan H, Zhou W, He W, Liu X, Ding Q, Ling L et al (2012) Genistein inhibits MDA-MB-231 triple-negative breast cancer cell growth by inhibiting NF-κB activity via the Notch-1 pathway. Int J Mol Med 30(2):337–343

    Article  CAS  PubMed  Google Scholar 

  183. Preet R, Mohapatra P, Mohanty S, Sahu SK, Choudhuri T, Wyatt MD, Kundu CN (2012) Quinacrine has anticancer activity in breast cancer cells through inhibition of topoisomerase activity. Int J Cancer 130(7):1660–1670

    Article  CAS  PubMed  Google Scholar 

  184. Preet R, Mohapatra P, Das D, Satapathy SR, Choudhuri T, Wyatt MD, Kundu CN (2013) Lycopene synergistically enhances quinacrine action to inhibit Wnt-TCF signaling in breast cancer cells through APC. Carcinogenesis 34(2):277–286

    Article  CAS  PubMed  Google Scholar 

  185. Li H, Yang B, Huang J, Xiang T, Yin X, Wan J, Luo F, Zhang L, Li H, Ren G (2013) Naringin inhibits growth potential of human triple-negative breast cancer cells by targeting β-catenin signaling pathway. Toxicol Lett 220(3):219–228. https://doi.org/10.1016/j.toxlet.2013.05.006

    Article  CAS  PubMed  Google Scholar 

  186. Xue M, Ge Y, Zhang J, Liu Y, Wang Q, Hou L, Zheng Z (2013) Fucoidan inhibited 4T1 mouse breast cancer cell growth in vivo and in vitro via downregulation of Wnt/β-catenin signaling. Nutr Cancer 65(3):460–468

    Article  CAS  PubMed  Google Scholar 

  187. Fu Y, Chang H, Peng X, Bai Q, Yi L, Zhou Y, Zhu J, Mi M (2014) Resveratrol inhibits breast cancer stem-like cells and induces autophagy via suppressing Wnt/β-catenin signaling pathway. PLoS ONE 9(7):e102535. https://doi.org/10.1371/journal.pone.0102535

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  188. Lu W, Lin C, Li Y (2014) Rottlerin induces Wnt co-receptor LRP6 degradation and suppresses both Wnt/β-catenin and mTORC1 signaling in prostate and breast cancer cells. Cell Signal 26(6):1303–1309. https://doi.org/10.1016/j.cellsig.2014.02.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Greenshields AL, Doucette CD, Sutton KM, Madera L, Annan H, Yaffe PB et al (2015) Piperine inhibits the growth and motility of triple-negative breast cancer cells. Cancer Lett 357(1):129–140

    Article  CAS  PubMed  Google Scholar 

  190. Srinivasan A, Thangavel C, Liu Y, Shoyele S, Den RB, Selvakumar P, Lakshmikuttyamma A (2016) Quercetin regulates β-catenin signaling and reduces the migration of triple negative breast cancer. Mol Carcinog 55(5):743–756

    Article  CAS  PubMed  Google Scholar 

  191. Wang L, Li H, Yang S, Ma W, Liu M, Guo S et al (2016) Cyanidin-3-o-glucoside directly binds to ERα36 and inhibits EGFR-positive triple-negative breast cancer. Oncotarget 7(42):68864

    Article  PubMed  PubMed Central  Google Scholar 

  192. Zhou T, Zhang A, Kuang G, Gong X, Jiang R, Lin D, Li J, Li H, Zhang X, Wan J, Li H (2017) Baicalin inhibits the metastasis of highly aggressive breast cancer cells by reversing epithelial-to-mesenchymal transition by targeting β-catenin signaling. Oncol Rep 38(6):3599–3607. https://doi.org/10.3892/or.2017.6011

    Article  CAS  PubMed  Google Scholar 

  193. Shrivastava S, Jeengar MK, Thummuri D, Koval A, Katanaev VL, Marepally S, Naidu VGM (2017) Cardamonin, a chalcone, inhibits human triple negative breast cancer cell invasiveness by downregulation of Wnt/β-catenin signaling cascades and reversal of epithelial–mesenchymal transition. BioFactors 43(2):152–169

    Article  CAS  PubMed  Google Scholar 

  194. Fatima I, El-Ayachi I, Taotao L, Lillo MA, Krutilina R, Seagroves TN et al (2017) The natural compound Jatrophone interferes with Wnt/β-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer. PLoS ONE 12(12):e0189864

    Article  PubMed  PubMed Central  Google Scholar 

  195. Lin D, Kuang G, Wan J, Zhang X, Li H, Gong X, Li H (2017) Luteolin suppresses the metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via downregulation of β-catenin expression. Oncol Rep 37(2):895–902

    Article  CAS  PubMed  Google Scholar 

  196. Cai Y, Zhao B, Liang Q, Zhang Y, Cai J, Li G (2017) The selective effect of glycyrrhizin and glycyrrhetinic acid on topoisomerase IIα and apoptosis in combination with etoposide on triple negative breast cancer MDA-MB-231 cells. Eur J Pharmacol 809:87–97

    Article  CAS  PubMed  Google Scholar 

  197. Martin ACB, Fuzer AM, Becceneri AB, da Silva JA, Tomasin R, Denoyer D et al (2017) [10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo. Oncotarget 8(42):72260

    Article  PubMed  PubMed Central  Google Scholar 

  198. Wang J, Qi H, Zhang X, Si W, Xu F, Hou T, Zhou H, Wang A, Li G, Liu Y, Fang Y, Piao HL, Liang X (2018) Saikosaponin D from Radix Bupleuri suppresses triple-negative breast cancer cell growth by targeting β-catenin signaling. Biomed Pharmacother 108:724–733. https://doi.org/10.1016/j.biopha.2018.09.038

    Article  CAS  PubMed  Google Scholar 

  199. Yu S, Wang Z, Su Z, Song J, Zhou L, Sun Q et al (2018) Gigantol inhibits Wnt/β-catenin signaling and exhibits anticancer activity in breast cancer cells. BMC Complement Altern Med 18(1):1–8

    Article  CAS  Google Scholar 

  200. Gan RY, Li HB, Sui ZQ, Corke H (2018) Absorption, metabolism, anti-cancer effect and molecular targets of epigallocatechin gallate (EGCG): an updated review. Crit Rev Food Sci Nutr 58(6):924–941

    Article  CAS  PubMed  Google Scholar 

  201. Koval A, Pieme CA, Queiroz EF, Ragusa S, Ahmed K, Blagodatski A, Wolfender JL, Petrova TV, Katanaev VL (2018) Tannins from Syzygium guineense suppress Wnt signaling and proliferation of Wnt-dependent tumors through a direct effect on secreted Wnts. Cancer Lett 435:110–120. https://doi.org/10.1016/j.canlet.2018.08.003

    Article  CAS  PubMed  Google Scholar 

  202. Scolamiero G, Pazzini C, Bonafè F, Guarnieri C, Muscari C (2018) Effects of α-mangostin on viability, growth and cohesion of multicellular spheroids derived from human breast cancer cell lines. Int J Med Sci 15(1):23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Li YW, Xu J, Zhu GY, Huang ZJ, Lu Y, Li XQ et al (2018) Apigenin suppresses the stem cell-like properties of triple-negative breast cancer cells by inhibiting YAP/TAZ activity. Cell Death Discov 4(1):105

    Article  PubMed  PubMed Central  Google Scholar 

  204. Li J, Gong X, Jiang R, Lin D, Zhou T, Zhang A et al (2018) Fisetin inhibited growth and metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via PTEN/Akt/GSK3β signal pathway. Front Pharmacol. https://doi.org/10.3389/fphar.2018.00772

    Article  PubMed  PubMed Central  Google Scholar 

  205. Xu X, Rajamanicham V, Xu S, Liu Z, Yan T, Liang G et al (2019) Schisandrin A inhibits triple negative breast cancer cells by regulating Wnt/ER stress signaling pathway. Biomed Pharmacother 115:108922

    Article  CAS  PubMed  Google Scholar 

  206. Cruz-Lozano M, González-González A, Marchal JA, Muñoz-Muela E, Molina MP, Cara FE et al (2019) Hydroxytyrosol inhibits cancer stem cells and the metastatic capacity of triple-negative breast cancer cell lines by the simultaneous targeting of epithelial-to-mesenchymal transition, Wnt/β-catenin and TGFβ signaling pathways. Eur J Nutr 58:3207–3219

    Article  CAS  PubMed  Google Scholar 

  207. Vallée A, Lecarpentier Y, Vallée JN (2019) Curcumin: a therapeutic strategy in cancers by inhibiting the canonical WNT/β-catenin pathway. J Exp Clin Cancer Res 38(1):1–16

    Article  Google Scholar 

  208. Arzi L, Hoshyar R, Jafarzadeh N, Riazi G, Sadeghizadeh M (2020) Anti-metastatic properties of a potent herbal combination in cell and mice models of triple negative breast cancer. Life Sci 243:117245

    Article  CAS  PubMed  Google Scholar 

  209. Tang C, Gong L, Lvzi Xu, Qiu K, Zhang Z, Wan L (2020) Echinacoside inhibits breast cancer cells by suppressing the Wnt/β-catenin signaling pathway. Biochem Biophys Res Commun 526(1):170–175. https://doi.org/10.1016/j.bbrc.2020.03.050

    Article  CAS  PubMed  Google Scholar 

  210. Collard M, Gallagher PE, Tallant EA (2020) A polyphenol-rich extract from muscadine grapes inhibits triple-negative breast tumor growth. Integr Cancer Ther 19:1534735420917444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. El Khalki L, Maire V, Dubois T, Zyad A (2020) Berberine impairs the survival of triple negative breast cancer cells: cellular and molecular analyses. Molecules 25(3):506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Mykhailenko O, Petrikaitė V, Korinek M, El-Shazly M, Chen BH, Yen CH et al (2021) Bio-guided bioactive profiling and HPLC-DAD fingerprinting of Ukrainian saffron (Crocus sativus stigmas): moving from correlation toward causation. BMC Complement Med Ther 21:1–15

    Article  Google Scholar 

  213. Cui P, Wang S (2019) Application of microfluidic chip technology in pharmaceutical analysis: a review. J Pharm Anal 9(4):238–247. https://doi.org/10.1016/j.jpha.2018.12.001

    Article  PubMed  Google Scholar 

  214. Ashley GW, Henise J, Reid R, Santi DV (2013) Hydrogel drug delivery system with predictable and tunable drug release and degradation rates. Proc Natl Acad Sci USA 110(6):2318–2323. https://doi.org/10.1073/pnas.1215498110

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  215. Van Hove AH, Antonienko E, Burke K, Brown E, Benoit DS (2015) Temporally tunable, enzymatically responsive delivery of proangiogenic peptides from poly(ethylene glycol)hydrogels. Adv Healthc Mater 4(13):2002–2011. https://doi.org/10.1002/adhm.201500304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Lin CC, Metters AT (2006) Hydrogels in controlled release formulations: network design and mathematical modeling. Adv Drug Deliv Rev 58(12–13):1379–1408. https://doi.org/10.1016/j.addr.2006.09.004

    Article  CAS  PubMed  Google Scholar 

  217. Reid R, Sgobba M, Raveh B, Rastelli G, Sali A, Santi DV (2015) Analytical and simulation-based models for the drug release and gel-degradation in a tetra-PEG hydrogel drug-delivery system. Macromolecules 48(19):7359–7369. https://doi.org/10.1021/acs.macromol.5b01598

    Article  CAS  ADS  Google Scholar 

  218. Jiang M, Huang O, Zhang X, Xie Z, Shen A, Liu H, Geng M, Shen K (2013) Curcumin induces cell death and restores tamoxifen sensitivity in the antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9. Molecules 18(1):701–720. https://doi.org/10.3390/molecules18010701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Ahmad R, Srivastava AN, Khan MA (2015) Evaluation of in vitro anticancer activity of stem of Tinospora cordifolia against human breast cancer and Vero cell lines. J Med Plants Stud 3(4):33–37

    Google Scholar 

  220. Kang B, Yu D, Dai Y, Chang S, Chen D, Ding Y (2009) Cancer-cell targeting and photoacoustic therapy using carbon nanotubes as “bomb” agents. Small 5(11):1292–1301

    Article  CAS  PubMed  Google Scholar 

  221. Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO et al (2011) Photodynamic therapy of cancer: an update. CA Cancer J Clin 61(4):250–281

    Article  PubMed  PubMed Central  Google Scholar 

  222. Martin M, Ramos-Medina R, Bernat R, García-Saenz JA, Del Monte-Millan M, Alvarez E, Cebollero M, Moreno F, Gonzalez-Haba E, Bueno O, Romero P, Massarrah T, Echavarria I, Jerez Y, Herrero B, Gonzalez Del Val R, Lobato N, Rincon P, Palomero MI et al (2021) Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts. Sci Rep 11(1):7064. https://doi.org/10.1038/s41598-021-85962-4

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  223. Newick K, O’Brien S, Moon E, Albelda SM (2017) CAR T cell therapy for solid tumors. Annu Rev Med 68(1):139–152. https://doi.org/10.1146/annurev-med-062315-120245

    Article  CAS  PubMed  Google Scholar 

  224. Theofilopoulos AN, Baccala R, Beutler B, Kono DH (2005) Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 23:307–336. https://doi.org/10.1146/annurev.immunol.23.021704.115843

    Article  CAS  PubMed  Google Scholar 

  225. Sica G, Iacopino F, Lama G, Amadori D, Baroni M, Sardo FL, Malacarne P, Marchetti P, Pellegrini A, Zaniboni A, Robustelli della Cuna G (1993) Steroid receptor enhancement by natural interferon-B in advanced breast cancer. Eur J Cancer 29(3):329–333. https://doi.org/10.1016/0959-8049(93)90378-S

    Article  Google Scholar 

  226. Chalhou N, Baker SJ (2009) PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4:127–150. https://doi.org/10.1146/annurev.pathol.4.110807.092311

    Article  CAS  Google Scholar 

  227. Davi M, Tripathi S, Hughley R, He Q, Bae S, Karanam B, Martini R, Newman L, Colomb W, Grizzle W, Yates C (2018) AR negative triple-negative or “quadruple negative” breast cancers in African American women have an enriched basal and immune signature. PLoS ONE 13(6):e0196909. https://doi.org/10.1371/journal.pone.0196909

    Article  CAS  Google Scholar 

  228. Johansson I, Aaltonen KE, Ebbesson A, Grabau D, Wigerup C, Hedenfalk I, Rydén L (2012) Increased gene copy number of KIT and VEGFR2 at 4q12 in primary breast cancer is related to an aggressive phenotype and impaired prognosis. Genes Chromosom Cancer 51(4):375–383. https://doi.org/10.1002/gcc.21922

    Article  CAS  PubMed  Google Scholar 

  229. Lehman BD, Abramson VG, Sanders ME, Mayer EL, Haddad TC, Nanda R, Van Poznak C, Storniolo AM, Nangia JR, Gonzalez-Ericsson PI, Sanchez V, Johnson KN, Abramson RG, Chen SC, Shyr Y, Arteaga CL, Wolff AC, Pietenpol JA, Translational Breast Cancer Research Consortium (2020) TBCRC 032 IB/II multicentre study: molecular insights to AR antagonist and PI3K inhibitor efficacy in patients with. Clin Cancer Res 26(9):2111–2123, Ar.+. https://doi.org/10.1158/1078-0432.CCR-19-2170

  230. Liu Z, Liu J, Zhang L, Liao P, Song J, Bi X (2014) Silver(I)-catalyzed hydroazidation of ethynyl carbinols: synthesis of 2-azidoallyl alcohols. Angew Chem Int Ed 53:5305–5309

    Article  CAS  Google Scholar 

  231. Mayer EL, Wander SA, Regan MM, DeMichele A, Forero-Torres A, Rimawi MF et al (2018) Palbociclib after CDK and endocrine therapy (PACE): a randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pretreated ER+/HER2- metastatic breast cancer. J Clin Oncol 36(15):TPS1104-TPS

    Article  Google Scholar 

  232. Reddy GD, Brahmaiah V, Kavitha BY, Nethagani J, Palaparthi EC, Lebaka RR, Deepika G (2023) Role of epigenetics variation with focus on DNA methylation in triple-negative breast cancer patients. Arch Med Health Sci 11(1):96–110

    Article  Google Scholar 

  233. Ruan S, Zhang L, Chen J, Cao T, Yang Y, Liu Y, He Q, Gao F, Gao H (2015) Targeting delivery and deep penetration using multistage nanoparticles for triple-negative breast cancer. RSC Adv 5(79):64303–64317. https://doi.org/10.1039/C5RA12436K

    Article  CAS  ADS  Google Scholar 

  234. Schütz F, Stefanovic S, Mayer L, von Au A, Domschke C, Sohn C (2017) PD-1/PD-L1 pathway in breast cancer. Oncol Res Treat 40(5):294–297. https://doi.org/10.1159/000464353

    Article  CAS  PubMed  Google Scholar 

  235. Soppa U, Schumacher J, Florencio Ortiz V, Pasqualon T, Tejedor FJ, Becker W (2014) The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and cyclin D1 and induces cell cycle exit and neuronal differentiation. Cell Cycle 13(13):2084–2100. https://doi.org/10.4161/cc.29104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Su YJ, Wang XK, Li BJ (2015) S-phase kinase-associated protein 2 expression interference inhibits breast cancer cell proliferation. Genet Mol Res 14(3):9244–9252. https://doi.org/10.4238/2015.August.10.4

    Article  CAS  Google Scholar 

  237. Wang H, Sun D, Ji P, Mohler J, Zhu L (2008) An AR-Skp2 pathway for the proliferation of androgen-dependent prostate cancer cells. J Cell Sci 121(15):2578–2587. https://doi.org/10.1242/jcs.030742

    Article  CAS  PubMed  Google Scholar 

  238. Yang C, Nan H, Ma J, Jiang L, Guo Q, Han L, Zhang Y, Nan K, Guo H (2015) High Skp2/Low p57(Kip2) expression is associated with poor prognosis in human breast carcinoma. Breast Cancer 9(Suppl 1):13–21. https://doi.org/10.4137/BCBCR.S30101

    Article  PubMed  PubMed Central  Google Scholar 

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  1. Yashasvi Bhat and M. R. Thrishna have contributed equally to this work.

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  1. School of Bio Science and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India

    Yashasvi Bhat, M. R. Thrishna & Satarupa Banerjee

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Bhat, Y., Thrishna, M.R. & Banerjee, S. Molecular targets and therapeutic strategies for triple-negative breast cancer. Mol Biol Rep 50, 10535–10577 (2023). https://doi.org/10.1007/s11033-023-08868-6

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