Adipocytes are one of the main components of the breast and have been shown to play a role in tumor development. In line with this observation, a few chemopreventive agents have been tested for their efficacy against BC cells. Sulforaphane, which is a compound present in broccoli, has been extensively studied and shown promising results.152 However, the limited understanding about the role of adipocytes in promoting tumorigenesis is limiting the scope of available options to target these adipocytes. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a well-known death receptor that can mediate ligand (TRAIL-R1, TRAIL-R2)-induced apoptosis, in tumor cells. TRAIL-mediated therapies are in Phase I clinical trials for TNBC.153 It has been reported that TRAIL can be a valuable tool for targeting patients who have limited treatment options.153 However, there are some tumors that show resistance to TRAIL therapy, with CSC being major contributors in therapy resistance. The overexpression of anti-apoptosis proteins like c-FLIP can lead to the resistance of anti-TRAIL therapy. Thus combining the c-FLIP inhibition with anti-TRAIL antibodies can lead to an effective eradiation of CSC and thus overcoming therapy resistance.154

Also, the macrophages and monocytes express a large amount of TRAIL receptors, that is, TRAIL-1R and TRAIL-2R. Thus, recombinant TRAIL therapy can help in selectively inducing apoptosis of the tumor-associated macrophages (TAM), which form a primary signaling arm for tumor microenvironment. Therefore, TRAIL therapy can provide dual benefits all together, where it can selectively eliminate tumor cells and also control the pro-tumor signals coming from TAM present in the microenvironment (Figure 4).155

Targeting CSC metabolism

CSCs show a distinct dependency on glucose and mitochondrial metabolism. It is shown that the multipotent cells rely majorly on glycolysis. The stem cell pool of basal-like BC, which is CD44+/EPCAM+, is dependent on aerobic glycolysis. Overexpression of FBP1, which promotes gluconeogenesis and inhibits glycolysis, reduces the number of spheroids in basal-like BC.156 A well-known regulator for mitochondrial metabolism is BCL-2 protein, which forms a complex with Bcl-2-associated death promoter and glucokinase. Inhibition of BCL-2 activation can lead to the inhibition of oxidative phosphorylation (OXPHOS) leading to the reduction of CSC depending on OXPHOS.157Increase in mitochondrial activity can promote metastasis and confer resistance to DNA damage in BC.158 A transcription factor peroxisome proliferator-activated receptor gamma, co-activator 1 alpha (PPARGC1A, also known as PGC-1α), is an important target for cancer cell metabolism as it couples with OXPHOS and supports migration and invasion of cells. This factor has been reported to be highly expressed in BCSCs and its inhibition lead to decreased stemness.159 Fatty acid oxidation is another major arm of supporting tumor cell growth and proliferation. It has been reported that various stem cell pools rely on fatty acid oxidation.160 NANOG is known to repress OXPHOS and activate fatty acid oxidation. Thus using etomoxir, a carnitine palmitoyltransferase-1 inhibitor, could reduce the spheroid formation ability of BC in vitro and also reduced in vivo tumorigenic potential.161 A mitochondria inhibitor VLX600 has been reported to target the quiescent cell pool within the tumor, in vivo.162Salinomycin, which is an antibiotic extracted from Streptomyces albus has been shown to reduce the stemness by targeting the Wnt pathway, which is crucial for maintaining stem cell proliferation.163Wnt signaling is a known regulator of cell metabolism, where a study has shown that using a therapeutic approach of administering Wnt antagonist frizzled-related protein 4 caused metabolic reprogramming, which led to apoptosis of CSC under variable glucose conditions.164 Recent reports suggest that targeting iron metabolism can be fruitful in targeting CSC since altered iron metabolism can cause increase in ROS and oxidative stress.165

Nano-therapeutics against CSC

Nanoparticle (NP)-mediated therapy is an effective strategy of drug delivery for cancer therapeutics. NPs are also being employed for targeting stem cell subpopulations within tumor bulk, where CSC marker-targeted NPs offer an advantage of specificity and precision. Thus using biocompatible polymers like liposome, PLGA, and so on, which are coated with antibodies/aptamers against BCSC-specific markers, can help in specific delivery of chemotherapeutic drug, RNAi, or antibodies to the stem cell population. BCSCs generally show enhanced expression of CD44, and studies have shown that paclitaxel- and salinomycin-loaded liposomal NP coated with CD44 antibody can target the CD44+ CSC population of MDA-MB-231 cells.166 Iron oxide magnetic NPs coated with CD44 antibody and loaded with gemcitabine have been used for targeting the stem cell population in BC.167 These particles have been shown to have an added advantage of hyperthermia. NPs containing a combination of chemotherapeutic agents along with autophagy inhibitor chloroquine (CQ) are an upcoming line of therapy which can target the tumor bulk as well as CSC pool within a tumor.168Doxorubicin and CQ NP have shown to reduce the ALDH high population of MDA-MB-231 cells.

Administration of decitabine, a DNA hypermethylation inhibitor encapsulated in NP made with polyethylene glycol, could sensitize the tumor bulk and CSC population to chemotherapy. Also, when these NPs were combined with doxorubicin, they could reduce the ALDH+ population in mammospheres of MDA-MB-231 cells.169 Anticancer drugs are frequently being incorporated into liposomes, for efficient drug delivery. An anticancer compound ESC8 was used along with dexamethasone (Dex)-associated liposome (DX), to form ESC8-entrapped liposome named DXE, showed promising results in reducing the drug-resistant cell population.170 Drug targets against Notch, TGF-β, and Wnt/β-catenin pathways are also being used in combination with NPs.

NPs are also used to deliver siRNA to tumor. A cationic lipid-based polymer was developed along with an siRNA and TGF-βR-I receptor inhibitor LY364947.171 Similarly, a cationic liposomal delivery of miR-34a could reduce the expression of CSC markers ALDH and CD44, thereby delaying tumor growth.172An interesting observation made by a group showed that graphene oxide (carbon nanomaterial) itself has the potential to induce differentiation of stem cells and reducing their in vitro sphere forming ability, thereby it can be a good source to target tumor bulk as well as the CSC population.173 Carbon nanotubes are capable of mediating a thermal effect, and they have been studied in BC cells where the BCSCs were found to be sensitive to these carbon nanotube thermal therapy.174 Further, conjugation of these carbon-based nanomaterials with stem cell receptor targeting can help achieve specificity. Also, novel methods of gene delivery using NPs are being effectively used to reduce tumor burden. An interesting study showed that specific gene delivery targeting the glucocorticoid receptor using a cationic liposome has the potential to reduce tumor growth in vivo.175


BC is a complex and heterogeneous disease, a culmination of a variety of cells that exert influence on one another, thereby making the disease management complex. Cellular/clonal heterogeneity within tumors and disease relapse are the major threats from the clinical point of view. We have now started to understand the quiescent, self-renewable pool of cells within a tumor population, the so-called BCSCs, which can govern the therapy resistance, metastasis, and disease relapse. Also the stem cells have unique mechanisms to withstand drug/radiation insults, for example, presence of large number of drug efflux pumps, and enhanced DNA repair machinery and thus posing big in terms of future developments of cancer therapeutics.

Tumor microenvironment is another key domain helping in maintenance of CSCs. Various elements like cytokine flux, tumor-associated immune cells, stromal cells, and CAFs impact chemokine receptor signaling, cytoskeletal rearrangements, hypoxia, angiogenesis, as well as cell metabolism. Altered cancer cell metabolism is a consequence of cancer condition where the BCSCs depend particularly on glycolysis. Mitochondrial OXPHOS is an alternative backup for stem cell survival. A large number of preclinical and clinical studies are being conducted on today’s date, targeting eradication of stem cell pool at the tumor site. Studies have also begun to explain the concept of CSC plasticity, where the non-CSCs can revert back to CSCs, and therefore, greater attention is needed as it will be indispensable for CSC management. The advancement in nanotherapeutics and nanomedicine is also greatly changing the face of treatment options by providing novel approaches of combining multimode treatment options. Together, all these dimensions added to BC research is surely going to give us an edge in reducing the impact of therapy resistance and improve disease outcomes in future days.


The authors report no conflicts of interest in this work.

Pranay Dey,1,2 Maitreyi Rathod,1,2 Abhijit De1,2
1Molecular Functional Imaging Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India; 2Molecular Functional Imaging Lab, Homi Bhabha National Institute, Mumbai, India


1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.

2. Curtis C, Shah SP, Chin S-F, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–352.

3. Centers for Disease Control and Prevention. Cancers diagnosed at late-stages despite available screening tests[Press release]. Available from: Accessed February 18, 2019.

4. Haque R, Ahmed SA, Inzhakova G, et al. Impact of breast cancer subtypes and treatment on survival: an analysis spanning two decades. Cancer Epidemiol Biomarkers Prev. 2012;21(10):1848–1855.

5. Reinert T, Barrios CH. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol. 2015;7(6):304–320.

6. Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367(5):435–444.

7. Wuerstlein R, Harbeck N. Neoadjuvant therapy for HER2-positive breast cancer. Rev Recent Clin Trials. 2017;12(2):81–92.

8. 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.

9. Berrada N, Delaloge S, André F. Treatment of triple-negative metastatic breast cancer: toward individualized targeted treatments or chemosensitization? Ann Oncol. 2010;21(Suppl 7):vii30–vii35.

10. Miller TW, Hennessy BT, González-Angulo AM, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406–2413.

11. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):224.

12. Blackwell K, Burris H, Gomez P, et al. Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor. Breast Cancer Res Treat. 2015;154(2):287–297.

13. di Leo A, Seok Lee K, Ciruelos E, et al. Abstract S4-07: BELLE-3: a phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2–, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment. Cancer Res. 2017;77(4 Supplement): S4-07.

14. Baselga J, Cortés J, Delaurentiis M, et al. SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA- mutant tumors. J Clin Oncol. 2017;35(15_suppl):TPS1119.

15. Saura C, de Azambuja E, Hlauschek D, et al. LBA10_PRPrimary results of LORELEI: a phase II randomized, double-blind study of neoadjuvant letrozole (let) plus taselisib versus let plus placebo (Pla) in postmenopausal patients (PTS) with ER+/HER2-negative early breast cancer (EBC). Ann Oncol. 2017;28(suppl_5):mdx440.001.

16. Schmid P, Pinder SE, Wheatley D, et al. Phase II randomized preoperative Window-of-Opportunity study of the PI3K inhibitor Pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2016;34(17):1987–1994.

17. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–529.

18. Fleming GF, Ma CX, Huo D, et al. Phase II trial of temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat. 2012;136(2):355–363.

19. Xu H, Yu S, Liu Q, et al. Recent advances of highly selective CDK4/6 inhibitors in breast cancer. J Hematol Oncol. 2017;10(1):97.

20. Shah AN, Cristofanilli M. The growing role of Cdk4/6 inhibitors in treating hormone receptor-positive advanced breast cancer. Curr Treat Options Oncol. 2017;18(1):6.

21. Barroso-Sousa R, Shapiro GI, Tolaney SM. Clinical development of the CDK4/6 inhibitors Ribociclib and Abemaciclib in breast cancer. Breast Care. 2016;11(3):167–173.

22. Sledge GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875–2884.

23. Acharya MR, Sparreboom A, Venitz J, Figg WD. Rational development of histone deacetylase inhibitors as anticancer agents: a review. Mol Pharmacol. 2005;68(4):917–932.

24. Stanway SJ, Delavault P, Purohit A, et al. Steroid sulfatase: a new target for the endocrine therapy of breast cancer. Oncologist. 2007;12(4):370–374.

25. Palmieri C, Stein RC, Liu X, et al. Iris study: a phase II study of the steroid sulfatase inhibitor irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients. Breast Cancer Res Treat. 2017;165(2):343–353.

26. Rasmussen LM, Zaveri NT, Stenvang J, Peters RH, Lykkesfeldt AE. A novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a promising agent for the therapy of breast cancer. Breast Cancer Res Treat. 2007;106(2):191–203.

27. Guerin M, Rezai K, Isambert N, et al. PIKHER2: a phase Ib study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer. Eur J Cancer. 2017;86:28–36.

28. Saura C, Bendell J, Jerusalem G, et al. Phase Ib study of Buparlisib plus trastuzumab in patients with HER2-positive advanced or metastatic breast cancer that has progressed on trastuzumab-based therapy. Clin Cancer Res. 2014;20(7):1935–1945.

29. Tolaney S, Burris H, Gartner E, et al. Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2015;149(1):151–161.

30. Hudis C, Swanton C, Janjigian YY, et al. A phase 1 study evaluating the combination of an allosteric Akt inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors. Breast Cancer Res. 2013;15(6):R110.

31. Hurvitz SA, Andre F, Jiang Z, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015;16(7):816–829.

32. Acevedo-Gadea C, Hatzis C, Chung G, et al. Sirolimus and trastuzumab combination therapy for HER2-positive metastatic breast cancer after progression on prior trastuzumab therapy. Breast Cancer Res Treat. 2015;150(1):157–167.

33. Seiler M, Ray-Coquard I, Melichar B, et al. Oral ridaforolimus plus trastuzumab for patients with HER2+ trastuzumab-refractory metastatic breast cancer. Clin Breast Cancer. 2015;15(1):60–65.

34. Nahta R, Esteva FJ. HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res. 2006;8(6):215.

35. Hettman T, Schneider M, Blum S, et al. Abstract B161: U3-1287 (AMG 888), a fully human anti-HER3 mAb, demonstrates preclinical efficacy in HER2+ and HER2- breast cancer models. Mol Cancer Ther. 2009;8(Supplement 1):B161.

36. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367–377.

37. Mukai H, Saeki T, Aogi K, et al. Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. Cancer Sci. 2016;107(10):1465–1470.

38. Bang YJ, Giaccone G, Im SA, et al. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol. 2017;28:855–861.

39. Diéras V, Bachelot T. The success story of trastuzumab emtansine, a targeted therapy in HER2-positive breast cancer. Target Oncol. 2014;9(2):111–122.

40. Lianos GD, Vlachos K, Zoras O, Roukos DH, et al. Potential of antibody-drug conjugates and novel therapeutics in breast cancer management. Onco Targets Ther. 2014;7:491.

41. Mittendorf EA, Clifton GT, Holmes JP, et al. Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients. Ann Oncol. 2014;25(9):1735–1742.

42. Limentani SA, Campone M, Dorval T, et al. A non-randomized dose-escalation phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors. Breast Cancer Res Treat. 2016;156(2):319–330.

43. Hamilton E, Blackwell K, Hobeika AC, et al. Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected]. J Transl Med. 2012;10:28.

44. Linderholm BK, Hellborg H, Johansson U, et al. Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol. 2009;20(10):1639–1646.

45. Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29(10):1252–1260.

46. Castrellon AB, Pidhorecky I, Valero V, Raez LE. The role of carboplatin in the neoadjuvant chemotherapy treatment of triple negative breast cancer. Oncol Rev. 2017;11(1).

47. Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017;377(6):523–533.

48. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–917.

49. Brown JS, Kaye SB, Yap TA. PARP inhibitors: the race is on. Br J Cancer. 2016;114(7):713–715.

50. Turner NC, Telli ML, Rugo HS, et al. Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO). J Clin Oncol. 2017;35(15_suppl):1007.

51. Timms KM, Abkevich V, Hughes E, et al. Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 2014;16(6):475.

52. Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol. 2012;30(21):2615–2623.

53. Baselga J, Gómez P, Greil R, et al. Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2013;31(20):2586–2592.

54. Tomao F, Papa A, Zaccarelli E, et al. Triple-negative breast cancer: new perspectives for targeted therapies. Onco Targets Ther. 2015;8:177.

55. Finn RS, Bengala C, Ibrahim N, et al. Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res. 2011;17(21):6905–6913.

56. Kim EM, Mueller K, Gartner E, Boerner J. Dasatinib is synergistic with cetuximab and cisplatin in triple-negative breast cancer cells. J Surg Res. 2013;185(1):231–239.

57. Rose AAN, Biondini M, Curiel R, Siegel PM. Targeting GPNMB with glembatumumab vedotin: current developments and future opportunities for the treatment of cancer. Pharmacol Ther. 2017;179:127–141.

58. Rose AA, Grosset AA, Dong Z, et al. Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer. Clin Cancer Res. 2010;16(7):2147–2156.

59. Yardley DA, Weaver R, Melisko ME, et al. Emerge: a randomized phase II study of the antibody-drug conjugate Glembatumumab Vedotin in advanced glycoprotein NMB-Expressing breast cancer. J Clin Oncol. 2015;33(14):1609–1619.

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

61. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–28.

62. Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14(3):275–291.

63. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100(7):3983–3988.

64. Chekhun SV, Zadvorny TV, Tymovska YO, et al. CD44+/CD24- markers of cancer stem cells in patients with breast cancer of different molecular subtypes. Exp Oncol. 2015;37(1):58–63.

65. Muñoz P, Iliou MS, Esteller M. Epigenetic alterations involved in cancer stem cell reprogramming. Mol Oncol. 2012;6(6):620–636.

66. Ling L, Nurcombe V, Cool SM. Wnt signaling controls the fate of mesenchymal stem cells. Gene. 2009;433(1–2):1–7.

67. Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006;66(12):6063–6071.

68. Rizzo P, Osipo C, Foreman K, et al. Rational targeting of Notch signaling in cancer. Oncogene. 2008;27(38):5124–5131.

69. Farnie G, Clarke RB. Mammary stem cells and breast cancer–role of Notch signalling. Stem Cell Rev. 2007;3(2):169–175.

70. Yamanaka S. Induction of pluripotent stem cells from mouse fibroblasts by four transcription factors. Cell Prolif. 2008;41(Suppl 1):51–56.

71. Rodriguez-Pinilla SM, Sarrio D, Moreno-Bueno G, et al. Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer. Mod Pathol. 2007;20(4):474–481.

72. Zhang J, Liang Q, Lei Y, et al. SOX4 induces epithelial-mesenchymal transition and contributes to breast cancer progression. Cancer Res. 2012;72(17):4597–4608.

73. Saitoh M. Involvement of partial EMT in cancer progression. J Biochem. 2018;164(4):257–264.

74. O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445(7123):106–110.

75. Chuthapisith S, Eremin J, El-Sheemey M, Eremin O. Breast cancer chemoresistance: emerging importance of cancer stem cells. Surg Oncol. 2010;19(1):27–32.

76. Rebucci M, Michiels C. Molecular aspects of cancer cell resistance to chemotherapy. Biochem Pharmacol. 2013;85(9):1219–1226.

77. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA. 2004;101(39):14228–14233.

78. Hu C, Li H, Li J, et al. Analysis of ABCG2 expression and side population identifies intrinsic drug efflux in the HCC cell line MHCC-97L and its modulation by Akt signaling. Carcinogenesis. 2008;29(12):2289–2297.

79. Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555–567.

80. Croker AK, Allan AL. Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44+ human breast cancer cells. Breast Cancer Res Treat. 2012;133(1):75–87.

81. Economopoulou P, Kaklamani VG, Siziopikou K. The role of cancer stem cells in breast cancer initiation and progression: potential cancer stem cell-directed therapies. Oncologist. 2012;17(11):1394–1401.

82. Charafe-Jauffret E, Ginestier C, Iovino F, et al. Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res. 2010;16(1):45–55.

83. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17(3):313–319.

84. Maugeri-Saccà M, Vigneri P, de Maria R. Cancer stem cells and chemosensitivity. Clin Cancer Res. 2011;17(15):4942–4947.

85. Eyler CE, Rich JN. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol. 2008;26(17):2839–2845.

86. Li H, Liu L, Guo L, et al. HERG K+ channel expression in CD34+/CD38-/CD123(high) cells and primary leukemia cells and analysis of its regulation in leukemia cells. Int J Hematol. 2008;87(4):387–392.

87. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645–648.

88. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730–737.

89. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65(23):10946–10951.

90. Bapat SA, Mali AM, Koppikar CB, Kurrey NK. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res. 2005;65(8):3025–3029.

91. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.

92. Creighton CJ, Li X, Landis M, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 2009;106(33):13820–13825.

93. Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017;14(10):611–629.

94. Desai S, Barai A, Bukhari AB, De A, Sen S. α-Actinin-4 confers radioresistance coupled invasiveness in breast cancer cells through AKT pathway. Biochim Biophys Acta Mol Cell Res. 2018;1865(1):196–208.

95. Gupta S, Iljin K, Sara H, et al. FZD4 as a mediator of ERG oncogene-induced Wnt signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 2010;70(17):6735–6745.

96. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449(7162):557–563.

97. Liu S, Ginestier C, Ou SJ, et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res. 2011;71(2):614–624.

98. Lim PK, Bliss SA, Patel SA, et al. Gap junction-mediated import of microRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. Cancer Res. 2011;71(5):1550–1560.

99. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–147.

100. Gabbiani G, Majno G. Dupuytren’s contracture: fibroblast contraction? An ultrastructural study. Am J Pathol. 1972;66(1):131–146.

101. Stuelten CH, Barbul A, Busch JI, et al. Acute wounds accelerate tumorigenesis by a T cell-dependent mechanism. Cancer Res. 2008;68(18):7278–7282.

102. Hu M, Yao J, Cai L, et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet. 2005;37(8):899–905.

103. Farmer P, Bonnefoi H, Anderle P, et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med. 2009;15(1):68–74.

104. Finak G, Bertos N, Pepin F, et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 2008;14(5):518–527.

105. Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6(7):506–520.

106. Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–348.

107. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107(5):1761–1767.

108. Chu QD, Panu L, Holm NT, et al. High chemokine receptor CXCR4 level in triple negative breast cancer specimens predicts poor clinical outcome. J Surg Res. 2010;159(2):689–695.

109. Scheller J, Rose-John S. Interleukin-6 and its receptor: from bench to bedside. Med Microbiol Immunol. 2006;195(4):173–183.

110. Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008;14(21):6735–6741.

111. Chao MP, Alizadeh AA, Tang C, et al. Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Cancer Res. 2011;71(4):1374–1384.

112. Benoy IH, Salgado R, van Dam P, et al. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clin Cancer Res. 2004;10(21):7157–7162.

113. Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46(7):1223–1231.

114. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, let-7 microRNA, and IL6 links inflammation to cell transformation. Cell. 2009;139(4):693–706.

115. Ginestier C, Liu S, Diebel ME, et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest. 2010;120(2):485–497.

116. Barnes PJ, Karin M. Nuclear factor-κB – a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997;336(15):1066–1071.

117. Michieli P, Mazzone M, Basilico C, et al. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell. 2004;6(1):61–73.

118. Vermeulen L, de Sousa E Melo F, van der Heijden M, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12(5):468–476.

119. Fillmore CM, Gupta PB, Rudnick JA, et al. Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc Natl Acad Sci USA. 2010;107(50):21737–21742.

120. Dufraine J, Funahashi Y, Kitajewski J. Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene. 2008;27(38):5132–5137.

121. Hiscox S, Parr C, Nakamura T, et al. Inhibition of HGF/SF-induced breast cancer cell motility and invasion by the HGF/SF variant, NK4. Breast Cancer Res Treat. 2000;59(3):245–254.

122. Lebedis C, Chen K, Fallavollita L, Boutros T, Brodt P. Peripheral lymph node stromal cells can promote growth and tumorigenicity of breast carcinoma cells through the release of IGF-I and EGF. Int J Cancer. 2002;100(1):2–8.

123. Pietras K, Rubin K, Sjöblom T, et al. Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res. 2002;62(19):5476–5484.

124. Singer CF, Kronsteiner N, Marton E, et al. MMP-2 and MMP-9 expression in breast cancer-derived human fibroblasts is differentially regulated by stromal-epithelial interactions. Breast Cancer Res Treat. 2002;72(1):69–77.

125. Dale TC, Weber-Hall SJ, Smith K, et al. Compartment switching of Wnt-2 expression in human breast tumors. Cancer Res. 1996;56(19):4320–4323.

126. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25(6):977–988.

127. Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11(1):69–82.

128. Bhati R, Patterson C, Livasy CA, et al. Molecular characterization of human breast tumor vascular cells. Am J Pathol. 2008;172(5):1381–1390.

129. Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007;129(3):465–472.

130. Holash J, Wiegand SJ, Yancopoulos GD. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene. 1999;18(38):5356–5362.

131. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med Overseas Ed. 2007;357(26):2666–2676.

132. Petrelli F, Barni S. Bevacizumab in advanced breast cancer: an opportunity as second-line therapy? Med Oncol. 2012;29(1):1–4.

133. Pàez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220–231.

134. Ebos JM, Lee CR, Cruz-Munoz W, et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15(3):232–239.

135. Santos SJ, Kakarala P, Heath A, Clouthier S, Wicha MS. Abstract 3336: anti-angiogenic agents increase breast cancer stem cells via generation of tumor hypoxia. Cancer Res. 2011;71(8 Supplement):3336.

136. Shojaei F, Lee JH, Simmons BH, et al. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010;70(24):10090–10100.

137. Soriano JV, Uyttendaele H, Kitajewski J, Montesano R. Expression of an activated Notch4(int-3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro. Int J Cancer. 2000;86(5):652–659.

138. Uyttendaele H, Soriano JV, Montesano R, Kitajewski J. Notch4 and Wnt-1 proteins function to regulate branching morphogenesis of mammary epithelial cells in an opposing fashion. Dev Biol. 1998;196(2):204–217.

139. Coleman-Vaughan C, Mal A, De A, McCarthy JV. The $γ$-Secretase Protease Complexes in Neurodegeneration, Cancer and Immunity. In Chakraborti S, Dhalla NS, editors. Pathophysiological Aspects of Proteases. Singapore: Springer; 2017:47–87.

140. Milano J, Mckay J, Dagenais C, et al. Modulation of Notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci. 2004;82(1):341–358.

141. Real PJ, Ferrando AA. Notch inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia. 2009;23(8):1374–1377.

142. Tian H, Callahan CA, Dupree KJ, et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA. 2009;106(11):4254–4259.

143. von Hoff DD, Lorusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361(12):1164–1172.

144. Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117–127.

145. Korkaya H, Paulson A, Charafe-Jauffret E, et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol. 2009;7(6):e1000121.

146. Kochhar R, Khurana V, Bejjanki H, Caldito G, Fort C. Statins to reduce breast cancer risk: a case control study in U.S. female veterans. J Clin Oncol. 2005;23(16_suppl):514–514.

147. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20–28.

148. Kastritis E, Charidimou A, Varkaris A, Dimopoulos MA. Targeted therapies in multiple myeloma. Targ Oncol. 2009;4(1):23–36.

149. Mercier I, Casimiro MC, Wang C, et al. Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 down-regulation and Rb tumor suppressor functional inactivation: implications for the response to hormonal therapy. Cancer Biol Ther. 2008;7(8):1212–1225.

150. Dittmer A, Fuchs A, Oerlecke I, et al. Mesenchymal stem cells and carcinoma-associated fibroblasts sensitize breast cancer cells in 3D cultures to kinase inhibitors. Int J Oncol. 2011;39(3):689–696.

151. Lu X, Kang Y. Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J Biol Chem. 2009;284(42):29087–29096.

152. Li Q, Xia J, Yao Y, et al. Sulforaphane inhibits mammary adipogenesis by targeting adipose mesenchymal stem cells. Breast Cancer Res Treat. 2013;141(2):317–324.

153. Rahman M, Pumphrey JG, Lipkowitz S. The TRAIL to targeted therapy of breast cancer. Adv Cancer Res. 2009;103:43–73.

154. Piggott L, Omidvar N, Pérez SM, Eberl M, Clarkson RWE. Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL. Breast Cancer Res. 2011;13(5):R88.

155. Liguori M, Buracchi C, Pasqualini F, et al. Functional TRAIL receptors in monocytes and tumor-associated macrophages: a possible targeting pathway in the tumor microenvironment. Oncotarget. 2016;7(27):41662–41676.

156. de Francesco EM, Sotgia F, Lisanti MP. Cancer stem cells (CSCs): metabolic strategies for their identification and eradication. Biochem J. 2018;475(9):1611–1634.

157. Deshmukh A, Deshpande K, Arfuso F, Newsholme P, Dharmarajan A. Cancer stem cell metabolism: a potential target for cancer therapy. Mol Cancer. 2016;15(1):69.

158. Snyder V, Reed-Newman TC, Arnold L, Thomas SM, Anant S. Cancer stem cell metabolism and potential therapeutic targets. Front Oncol. 2018;8:203.

159. Sancho P, Burgos-Ramos E, Tavera A, et al. MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab. 2015;22(4):590–605.

160. Mancini R, Noto A, Pisanu ME, et al. Metabolic features of cancer stem cells: the emerging role of lipid metabolism. Oncogene. 2018;37(18):2367–2378.

161. de Francesco EM, Maggiolini M, Tanowitz HB, Sotgia F, Lisanti MP. Targeting hypoxic cancer stem cells (CSCs) with doxycycline: implications for optimizing anti-angiogenic therapy. Oncotarget. 2017;8(34):56126–56142.

162. Zhang X, Fryknäs M, Hernlund E, et al. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat Commun. 2014;5(1):3295.

163. Jangamreddy JR, Ghavami S, Grabarek J, et al. Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: differences between primary and cancer cells. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. 2013;1833(9):2057–2069.

164. Deshmukh A, Arfuso F, Newsholme P, Dharmarajan A. Regulation of cancer stem cell metabolism by secreted frizzled-related protein 4 (sFRP4). Cancers. 2018;10(2):40.

165. El Hout M, dos Santos L, Hamaï A, Mehrpour M. A promising new approach to cancer therapy: targeting iron metabolism in cancer stem cells. Semin Cancer Biol. 2018;53:125–138.

166. Wu D, Si M, Xue HY, Wong HL. Nanomedicine applications in the treatment of breast cancer: current state of the art. Int J Nanomedicine. 2017;12:5879–5892.

167. Hong IS, Jang GB, Lee HY, Nam JS. Targeting cancer stem cells by using the nanoparticles. Int J Nanomedicine. 2015;10(Spec Iss):251–260.

168. Sun R, Shen S, Zhang YJ, et al. Nanoparticle-facilitated autophagy inhibition promotes the efficacy of chemotherapeutics against breast cancer stem cells. Biomaterials. 2016;103:44–55.

169. Li SY, Sun R, Wang HX, et al. Combination therapy with epigenetic-targeted and chemotherapeutic drugs delivered by nanoparticles to enhance the chemotherapy response and overcome resistance by breast cancer stem cells. J Control Release. 2015;205:7–14.

170. Ahmad A, Mondal SK, Mukhopadhyay D, Banerjee R, Alkharfy KM. Development of liposomal formulation for delivering anticancer drug to breast cancer Stem-Cell-Like cells and its pharmacokinetics in an animal model. Mol Pharm. 2016;13(3):1081–1088.

171. Zuo ZQ, Chen KG, Yu XY, et al. Promoting tumor penetration of nanoparticles for cancer stem cell therapy by TGF-β signaling pathway inhibition. Biomaterials. 2016;82:48–59.

172. Pramanik D, Campbell NR, Karikari C, et al. Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Mol Cancer Ther. 2011;10(8):1470–1480.

173. Fiorillo M, Verre AF, Iliut M, et al. Graphene oxide selectively targets cancer stem cells, across multiple tumor types: implications for non-toxic cancer treatment, via “differentiation-based nano-therapy”. Oncotarget. 2015;6(6):3553–3562.

174. Burke AR, Singh RN, Carroll DL, et al. The resistance of breast cancer stem cells to conventional hyperthermia and their sensitivity to nanoparticle-mediated photothermal therapy. Biomaterials. 2012;33(10):2961–2970.

175. Mukherjee A, Narayan KP, Pal K, et al. Selective cancer targeting via aberrant behavior of cancer cell-associated glucocorticoid receptor. Mol Ther. 2009;17(4):623–631.

Source: Breast Cancer: Targets and Therapy.
Originally published March 7, 2019.