Tackling heterogeneity in treatment-resistant breast cancer using a broad-spectrum therapeutic approach

Abstract

Tumor heterogeneity can contribute to the development of therapeutic resistance in cancer, including advanced breast cancers. The object of the Halifax project was to identify new treatments that would address mechanisms of therapeutic resistance through tumor heterogeneity by uncovering combinations of therapeutics that could target the hallmarks of cancer rather than focusing on individual gene products. A taskforce of 180 cancer researchers, used molecular profiling to highlight key targets responsible for each of the hallmarks of cancer and then find existing therapeutic agents that could be used to reach those targets with limited toxicity. In many cases, natural health products and re-purposed pharmaceuticals were identified as potential agents. Hence, by combining the molecular profiling of tumors with therapeutics that target the hallmark features of cancer, the heterogeneity of advanced-stage breast cancers can be addressed.

Keywords

Breast cancer / chemoresistance / drug resistance / targeted therapy

References

[1] Mavrommati I,Echeverria GV.Subclonal heterogeneity and evolution in breast cancer.NPJ Breast Cancer2021;7:155 PMCID:PMC8692469

[2] Yang R,Wang H,Yin X.Therapeutic progress and challenges for triple negative breast cancer: targeted therapy and immunotherapy.Mol Biomed2022;3:8 PMCID:PMC8894518

[3] Turner KM,Holm TM,Guan JL.Heterogeneity within molecular subtypes of breast cancer.Am J Physiol Cell Physiol2021;321:C343-54 PMCID:PMC8424677

[4] Blucher AS,Tsang YH.Precision oncology for breast cancer through clinical trials.Clin Exp Metastasis2022;39:71-8

[5] Zambelli A,De Sanctis R,Santoro A.Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets.Expert Opin Ther Targets2022;26:557-73

[6] Pasha N.Understanding and overcoming tumor heterogeneity in metastatic breast cancer treatment.Nat Cancer2021;2:680-92

[7] Ferrari P,Ghilli M,Lorenzini G.Molecular mechanisms, biomarkers and emerging therapies for chemotherapy resistant TNBC.Int J Mol Sci2022;23:1665 PMCID:PMC8836182

[8] Li A,Parmar S.Characterizing advanced breast cancer heterogeneity and treatment resistance through serial biopsies and comprehensive analytics.NPJ Precis Oncol2021;5:28 PMCID:PMC7997873

[9] Zong Y.Research advances and new challenges in overcoming triple-negative breast cancer.Cancer Drug Resist2021;4:517-42 PMCID:PMC8654168

[10] Bishayee A.A broad-spectrum integrative design for cancer prevention and therapy: The challenge ahead.Semin Cancer Biol2015;35 Suppl:S1-4

[11] Hanahan D.Hallmarks of cancer: the next generation.Cell2011;144:646-74

[12] Ferguson LR,Collins AR.Genomic instability in human cancer: molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition.Semin Cancer Biol2015;35 Suppl:S5-S24 PMCID:PMC4600419

[13] Feitelson MA,Kulathinal RJ.Sustained proliferation in cancer: mechanisms and novel therapeutic targets.Semin Cancer Biol2015;35 Suppl:S25-54 PMCID:PMC4898971

[14] Amin ARMR,Carey TE.Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds.Semin Cancer Biol2015;35 Suppl:S55-77 PMCID:PMC4561219

[15] Mohammad RM,Lowe L.Broad targeting of resistance to apoptosis in cancer.Semin Cancer Biol2015;35 Suppl:S78-S103 PMCID:PMC4720504

[16] Yaswen P,Keith WN.Therapeutic targeting of replicative immortality.Semin Cancer Biol2015;35 Suppl:S104-28 PMCID:PMC4600408

[17] Hirschey MD,Diehl AME.Target Validation TeamDysregulated metabolism contributes to oncogenesis.Semin Cancer Biol2015;35 Suppl:S129-50 PMCID:PMC4656121

[18] Samadi AK,Georgakilas AG.A multi-targeted approach to suppress tumor-promoting inflammation.Semin Cancer Biol2015;35 Suppl:S151-84 PMCID:PMC4635070

[19] Vinay DS,Pawelec G.Immune evasion in cancer: mechanistic basis and therapeutic strategies.Semin Cancer Biol2015;35 Suppl:S185-98

[20] Casey SC,Aquilano K.Cancer prevention and therapy through the modulation of the tumor microenvironment.Semin Cancer Biol2015;35 Suppl:S199-223 PMCID:PMC4930000

[21] Wang Z,Yin X.Broad targeting of angiogenesis for cancer prevention and therapy.Semin Cancer Biol2015;35 Suppl:S224-43 PMCID:PMC4737670

[22] Jiang WG,Katoh M.Tissue invasion and metastasis: molecular, biological and clinical perspectives.Semin Cancer Biol2015;35 Suppl:S244-75

[23] Block KI,Lowe L.Designing a broad-spectrum integrative approach for cancer prevention and treatment.Semin Cancer Biol2015;35 Suppl:S276-304 PMCID:PMC4819002

[24] Liao CL,Chen JC.Allyl isothiocyanate induces DNA damage and impairs DNA repair in human breast cancer MCF-7 cells.Anticancer Res2021;41:4343-51

[25] Geng A,Yao Y.Chrysin impairs genomic stability by suppressing DNA double-strand break repair in breast cancer cells.Cell Cycle2022;21:379-91 PMCID:PMC8855858

[26] Sameni S.Plumbagin triggers DNA damage response, telomere dysfunction and genome instability of human breast cancer cells.Biomed Pharmacother2016;82:256-68

[27] Kowsari H,Dashti F.Resveratrol in cancer treatment with a focus on breast cancer.Curr Mol Pharmacol2022;

[28] Yuri T,Tsujita-kyutoku M.Perillyl alcohol inhibits human breast cancer cell growth in vitro and in vivo.Breast Cancer Res Treat2004;84:251-60

[29] Guan X.Artemisinin induces selective and potent anticancer effects in drug resistant breast cancer cells by inducing cellular apoptosis and autophagy and G2/M cell cycle arrest.J BUON2020;25:1330-6

[30] Mahmoud MA,Omran GA.Rosmarinic acid suppresses inflammation, angiogenesis, and improves paclitaxel induced apoptosis in a breast cancer model via NF3 κB-p53-caspase-3 pathways modulation.J Appl Biomed2021;19:202-9

[31] Yao M,Yuan B.Berberine inhibits NLRP3 Inflammasome pathway in human triple-negative breast cancer MDA-MB-231 cell.BMC Complement Altern Med2019;19:216 PMCID:PMC6694465

[32] Song X,Dai E.Molecular targets of curcumin in breast cancer (Review).Mol Med Rep2019;19:23-9

[33] Banerjee N,Safe S.Cytotoxicity of pomegranate polyphenolics in breast cancer cells in vitro and vivo: potential role of miRNA-27a and miRNA-155 in cell survival and inflammation.Breast Cancer Res Treat2012;136:21-34 PMCID:PMC3488590

[34] Mehta R,Alimirah F.Deguelin action involves c-Met and EGFR signaling pathways in triple negative breast cancer cells.PLoS One2013;8:e65113 PMCID:PMC3677900

[35] Wu HT,Liu YE.Luteolin suppresses androgen receptor-positive triple-negative breast cancer cell proliferation and metastasis by epigenetic regulation of MMP9 expression via the AKT/mTOR signaling pathway.Phytomedicine2021;81:153437

[36] Kim SH,Arlotti JA.Withaferin a inhibits in vivo growth of breast cancer cells accelerated by Notch2 knockdown.Breast Cancer Res Treat2016;157:41-54 PMCID:PMC4867258

[37] Hahm ER,Singh KB,Singh SV.A comprehensive review and perspective on anticancer mechanisms of withaferin a in breast cancer.Cancer Prev Res (Phila)2020;13:721-34 PMCID:PMC7501947

[38] Cao X,Wang Y.Curcumin suppresses tumorigenesis by ferroptosis in breast cancer.PLoS One2022;17:e0261370 PMCID:PMC8765616

[39] Huang CY,Li X,Zhu SS.Mechanism of EGCG promoting apoptosis of MCF-7 cell line in human breast cancer.Oncol Lett2017;14:3623-7 PMCID:PMC5588052

[40] Messeha SS,Mendonca P,Cotton C.Effects of gossypol on apoptosis-related gene expression in racially distinct triple-negative breast cancer cells.Oncol Rep2019;42:467-78 PMCID:PMC6610046

[41] Gao H,Dong L.Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF-7 cells.Exp Ther Med2018;15:3413-9 PMCID:PMC5841063

[42] Yi X,Tan C.Kaempferol, a flavonoid compound from.gynura medica13:210-5 PMCID:PMC5566146

[43] Khalki L, Maire V, Dubois T, Zyad A. Berberine impairs the survival of triple negative breast cancer cells: cellular and molecular analyses.Molecules2020;25:506 PMCID:PMC7036777

[44] Zhu Y,Chai Y.Apoptosis induction, a sharp edge of berberine to exert anti-cancer effects, focus on breast, lung, and liver cancer.Front Pharmacol2022;13:803717 PMCID:PMC8830521

[45] Ávila-Gálvez MÁ,Martínez-Díaz F.Disposition of dietary polyphenols in breast cancer patients’ tumors, and their associated anticancer activity: the particular case of curcumin.Mol Nutr Food Res2021;65:e2100163

[46] Nasiri M,Koshki KN.Curcumin and silibinin inhibit telomerase expression in T47D human breast cancer cells.Asian Pac J Cancer Prev2013;14:3449-53

[47] Lee YH,Park KH.Coumestrol induces senescence through protein kinase CKII inhibition-mediated reactive oxygen species production in human breast cancer and colon cancer cells.Food Chem2013;141:381-8

[48] Lewinska A,Kwasniewicz E,Wnuk M.Diosmin-induced senescence, apoptosis and autophagy in breast cancer cells of different p53 status and ERK activity.Toxicol Lett2017;265:117-30

[49] Gomez LS,Marcondes MC.Resveratrol decreases breast cancer cell viability and glucose metabolism by inhibiting 6-phosphofructo-1-kinase.Biochimie2013;95:1336-43

[50] Shao S,An G.Metformin suppresses HIF-1α expression in cancer-associated fibroblasts to prevent tumor-stromal cross talk in breast cancer.FASEB J2020;34:10860-70

[51] Chen Y,Zhang M.Baicalein resensitizes tamoxifen-resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia-inducible factor-1α.Clin Transl Med2021;11:e577 PMCID:PMC8567056

[52] Chai XX,Wang JC.Carpesium abrotanoides (L.) root as a potential source of natural anticancer compounds: targeting glucose metabolism and PKM2/HIF-1α axis of breast cancer cells.J Food Sci2019;84:3825-32

[53] Li W,Wang S.Anti-tumor potential of astragalus polysaccharides on breast cancer cell line mediated by macrophage activation.Mater Sci Eng C Mater Biol Appl2019;98:685-95

[54] Jeong MH,Lee SW.Cordycepin-enriched Cordyceps militaris induces immunomodulation and tumor growth delay in mouse-derived breast cancer.Oncol Rep2013;30:1996-2002

[55] Pan J,Si W.Resveratrol promotes MICA/B expression and natural killer cell lysis of breast cancer cells by suppressing c-Myc/miR-17 pathway.Oncotarget2017;8:65743-58 PMCID:PMC5630368

[56] Bimonte S,Palma G.Dissecting the role of curcumin in tumour growth and angiogenesis in mouse model of human breast cancer.Biomed Res Int2015;2015:878134 PMCID:PMC4386568

[57] Gu JW,Tucker KB.EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1α and NFκB, and VEGF expression.Vasc Cell2013;5:9 PMCID:PMC3649947

[58] Karadas AK,Aytac G.Melatonin decreases metastasis, primary tumor growth and angiogenesis in a mice model of breast cancer.Hum Exp Toxicol2021;40:1545-57

[59] Alvarez-García V,Alonso-González C,Cos S.Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells.J Pineal Res2013;54:373-80

[60] Garvin S,Dabrosin C.Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo.Cancer Lett2006;231:113-22

[61] Wei Z,Tao L.Diallyl trisulfides, a natural histone deacetylase inhibitor, attenuate HIF-1α synthesis, and decreases breast cancer metastasis.Mol Carcinog2017;56:2317-31

[62] Sun Y,Lu YY.Resveratrol inhibits the migration and metastasis of MDA-MB-231 human breast cancer by reversing TGF-β1-induced epithelial-mesenchymal transition.Molecules2019;24:1131 PMCID:PMC6471699

[63] Zhou J,Chen XY.Black rice-derived anthocyanins inhibit HER-2-positive breast cancer epithelial-mesenchymal transition-mediated metastasis in vitro by suppressing FAK signaling.Int J Mol Med2017;40:1649-56 PMCID:PMC5716451

[64] Liu C,Li L,Wu X.Natural cordycepin induces apoptosis and suppresses metastasis in breast cancer cells by inhibiting the Hedgehog pathway.Food Funct2020;11:2107-16

[65] Cheuk IW,Siu M.Resveratrol enhanced chemosensitivity by reversing macrophage polarization in breast cancer.Clin Transl Oncol2022;24:854-63

[66] Li Q,Yao Y,Shi H.Sulforaphane inhibits mammary adipogenesis by targeting adipose mesenchymal stem cells.Breast Cancer Res Treat2013;141:317-24 PMCID:PMC3816005

[67] Rong Y,Yi K.Co-administration of sulforaphane and doxorubicin attenuates breast cancer growth by preventing the accumulation of myeloid-derived suppressor cells.Cancer Lett2020;493:189-96

[68] Farghadani R.Curcumin as an enhancer of therapeutic efficiency of chemotherapy drugs in breast cancer.Int J Mol Sci2022;23:2144 PMCID:PMC8878285

[69] Ávila-Gálvez MÁ,Espín JC.Dietary phenolics against breast cancer. A critical evidence-based review and future perspectives.Int J Mol Sci2020;21:5718 PMCID:PMC7461055

[70] Monisha J,Roy NK.NF-κB blockers gifted by mother nature: prospectives in cancer cell chemosensitization.Curr Pharm Des2016;22:4173-200

[71] Khatoon E,Harsha C.Phytochemicals in cancer cell chemosensitization: current knowledge and future perspectives.Semin Cancer Biol2022;80:306-39

[72] Ahire V,Mishra KP.Ellagic acid enhances apoptotic sensitivity of breast cancer cells to γ-radiation.Nutr Cancer2017;69:904-10

[73] Wang W,Huangfu C,Zhang J.3,3’-Diindolylmethane: a promising sensitizer of γ-irradiation.Biomed Res Int2015;2015:465105 PMCID:PMC4633530

[74] Wang J,Yang Q.Radiosensitization effects of berberine on human breast cancer cells.Int J Mol Med2012;30:1166-72

[75] Al-Abbasi FA,Baghdadi MA.Gingerol synergizes the cytotoxic effects of doxorubicin against liver cancer cells and protects from its vascular toxicity.Molecules2016;21:886 PMCID:PMC6274287

[76] Goel A.Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs.Nutr Cancer2010;62:919-30

[77] Angelis ML, Francescangeli F, Zeuner A. Breast cancer stem cells as drivers of tumor chemoresistance, dormancy and relapse: new challenges and therapeutic opportunities.Cancers (Basel)2019;11:1569 PMCID:PMC6826533

[78] Ke DYJ,Wang L.The potential of natural products in the treatment of triple-negative breast cancer.Curr Cancer Drug Targets2022;22:388-403

[79] Retsky M,Hrushesky WJ.Promising development from translational or perhaps anti-translational research in breast cancer.Clin Transl Med2012;1:17 PMCID:PMC3560986

[80] Retsky M,Hrushesky W.Breast cancer and the black swan.Ecancermedicalscience2020;14:1050 PMCID:PMC7289621

[81] Deng X.Cancer precision medicine: from cancer screening to drug selection and personalized immunotherapy.Trends Pharmacol Sci2017;38:15-24

[82] Paller CJ,Carducci MA.Challenges of conducting clinical trials of natural products to combat cancer.Clin Adv Hematol Oncol2016;14:447-55 PMCID:PMC8521639

[83] Frenkel M.The use of dietary supplements in oncology.Curr Oncol Rep2014;16:411

[84] Le TQ,Harnett J.A systematic review - biologically-based complementary medicine use by people living with cancer - is a more clearly defined role for the pharmacist required?.Res Social Adm Pharm2017;13:1037-44

[85] Yen C,Yu Z,Li CG.Interactions between natural products and tamoxifen in breast cancer: a comprehensive literature review.Front Pharmacol2022;13:847113 PMCID:PMC9201062

[86] Lopez G,Cohen L.Integrative oncology physician consultations at a comprehensive cancer center: analysis of demographic, clinical and patient reported outcomes.J Cancer2017;8:395-402 PMCID:PMC5332890

[87] Standish LJ,Sweet E.Breast cancer integrative oncology care and its costs.Integr Cancer Ther2017;16:85-95 PMCID:PMC5736066

[88] Dekkers OM,Altman DG.Distinguishing case series from cohort studies.Ann Intern Med2012;156:37-40