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Review

An Insight Into the Cancer Stem Cell Survival Pathways Involved in Chemoresistance in Triple-Negative Breast Cancer

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 4185-4206 | Received 08 Feb 2021, Accepted 06 Jul 2021, Published online: 03 Aug 2021

References

  • Sung H , FerlayJ, SiegelRLet al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin.71(3), 209–249 (2021).
  • Perou CM , SørlieT, EisenMBet al. Molecular portraits of human breast tumours. Nature406(6797), 747–752 (2000).
  • Sørlie T , PerouCM, TibshiraniRet al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA98(19), 10869–10874 (2001).
  • Sotiriou C , NeoSY, McShaneLMet al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc. Natl Acad. Sci. USA100(18), 10393–10398 (2003).
  • Siegel Rl , MillerKD, JemalA. Cancer statistics. CA Cancer J. Clin.69(1), 7–34 (2019).
  • Keegan TH , KurianAW, GaliKet al. Racial/ethnic and socioeconomic differences in short-term breast cancer survival among women in an integrated health system. Am. J. Public Health105(5), 938–946 (2015).
  • Iwata H , ImSeock-Ah, MasudaNet al. PALOMA-3: Phase III trial of fulvestrant with or without palbociclib in premenopausal and postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer that progressed on prior endocrine-therapy – safety and efficacy in Asian patients. J. Glob. Oncol.3(4), 289–303 (2017).
  • Vagia E , MahalingamD, CistofanilliM. The landscape of targeted therapies in TNBC. Cancers (Basel)12(4), 916 (2020).
  • Lebert JM , LesterR, PowellEet al. Advances in the systemic treatment of triple-negative breast cancer. Curr. Oncol.25(Suppl. 1), S142–S150 (2018).
  • Liedtke C , MazouniC, HessKRet al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J. Clin. Oncol.26(8), 1275–1281 (2008).
  • Carey LA , DeesE, SawyerLet al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin. Cancer Res.13(8), 2329–2334 (2007).
  • Li X , LewisMT, HuangJet al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl Cancer Inst.100(9), 672–679 (2008).
  • Zhou L , JiangY, YanTet al. The prognostic role of cancer stem cells in breast cancer: a meta-analysis of published literatures. Breast Cancer Res. Treat.122(3), 795–801 (2010).
  • Zou P , YoshiharaH, HosokawaKet al. p57Kip2 and p27Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell9(3), 247–261 (2011).
  • Wang T , FahrmannJF, LeeHet al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab.27(1), 136–150 (2018).
  • Pires BRB , DeAmorim ÍSS, SouzaLDE, RodriguesJA, MencalhaAL. Targeting cellular signaling pathways in breast cancer stem cells and its implication for cancer treatment. Anticancer Res.36(11), 5681–5691 (2016).
  • Cochrane CR , SzczepnyA, WatkinsDN, CainJE. Hedgehog signaling in the maintenance of cancer stem cells. Cancers (Basel)7(3), 1554–1585 (2015).
  • Wicking C , McglinnE. The role of hedgehog signalling in tumorigenesis. Cancer Lett.173(1), 1–7 (2001).
  • Dontu G , JacksonKW, McnicholasE, KawamuraMJ, AbdallahWM, WichaMS. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res.6(6), 1–11 (2004).
  • Gupta PB , OnderTT, JiangGet al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell138(4), 645–659 (2009).
  • Talukdar S , BhoopathiP, EmdadL, DasS, SarkarD, FisherPB. Dormancy and cancer stem cells: an enigma for cancer therapeutic targeting. Adv. Cancer Res.141, 43–84 (2019).
  • Ko CCH , ChiaWK, SelvarajahGT, CheahYK, WongYP, TanGC. The role of breast cancer stem cell-related biomarkers as prognostic factors. Diagnostics10(9), 721 (2020).
  • Song K , FarzanehM. Signaling pathways governing breast cancer stem cells behavior. Stem Cell. Res. Ther.12(1), 1–11 (2021).
  • Liu X , GaoJ, SunYet al. Mutation of N-linked glycosylation in EpCAM affected cell adhesion in breast cancer cells. Biol. Chem.398(10), 1119–1126 (2017).
  • Liu M , LiuY, DengLet al. Transcriptional profiles of different states of cancer stem cells in triple-negative breast cancer. Mol. Cancer17(1), 1–6 (2018).
  • Aponte PM , CaicedoA. Stemness in cancer: stem cells, cancer stem cells, and their microenvironment. Stem Cells Int.2017, 5619472 (2017).
  • Park S-Y , ChoiJ-H, NamJ-S. Targeting cancer stem cells in triple-negative breast cancer. Cancers (Basel)11(7), 965 (2019).
  • Longley DB , JohnstonPG. Molecular mechanisms of drug resistance. J. Pathol.205(2), 275–292 (2005).
  • Gottesman MM , PastanI. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem.62, 385–427 (1993).
  • Lobo NA , ShimonoY, QianD, ClarkeMF. The biology of cancer stem cells. Annu. Rev. Cell Dev. Biol.23, 675–699 (2007).
  • Yamada A , IshikawaT, OtaIet al. High expression of ATP-binding cassette transporter ABCC11 in breast tumors is associated with aggressive subtypes and low disease-free survival. Breast Cancer Res. Treat.137(3), 773–782 (2013).
  • Xu L , ZhaoZ, WangKet al. Expression of aldehyde dehydrogenase 1 and ATP-binding cassette superfamily G member 2 is enhanced in primary foci and metastatic lymph node from patients with triple-negative breast cancer. Biomed. Res.28, 5078–5083 (2017).
  • Chen Z , ShiT, ZhangL. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: a review of the past decade. Cancer Lett.370(1), 153–164 (2016).
  • Sissung TM , BaumC, KirklandCT, GaoR, GardnerER, FiggWD. Pharmacogenetics of membrane transporters: an update on current approaches. Mol. Biotechnol.44(2), 152–167 (2010).
  • Oguri T , BesshoY, AchiwaHet al. MRP8/ABCC11 directly confers resistance to 5-fluorouracil. Mol. Cancer Ther.6(1), 122–127 (2007).
  • Degorter MK , XiaCQ, YangJJ, KimRB. Drug transporters in drug efficacy and toxicity. Annu. Rev. Pharmacol. Toxicol.52, 249–273 (2012).
  • Goodell MA , BroseK, ParadisG, ConnerAS, MulliganRC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med.183(4), 1797–1806 (1996).
  • Chuthapisith S , EreminJ, El-SheemeyM, EreminO. Breast cancer chemoresistance: emerging importance of cancer stem cells. 19(1), 27–32 (2010).
  • Scharenberg CW , HarkeyMA, Torok-StorbB. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood99(2), 507–512 (2002).
  • Saxena M , StephensMA, PathakH, RangarajanA. Transcription factors that mediate epithelial–mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis.2(7), e179(2011).
  • Britton KM , EyreR, HarveyIJet al. Breast cancer, side population cells and ABCG2 expression. Cancer Lett.323(1), 97–105 (2012).
  • Arumugam A , SubramaniR, NandySBet al. Silencing growth hormone receptor inhibits estrogen receptor negative breast cancer through ATP-binding cassette sub-family G member 2. Exp. Mol. Med.51(1), 1–13 (2019).
  • Guestini F , OnoK, MiyashitaMet al. Impact of topoisomerase IIα, PTEN, ABCC1/MRP1, and KI67 on triple-negative breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res. Treat.173(2), 275–288 (2019).
  • Hawley TS , RizI, YangWet al. Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1. Am. J. Hematol.88(4), 265–272 (2013).
  • Mcintosh K , CurtB, TiwariAK. Tackling multidrug resistance mediated by efflux transporters in tumor-initiating cells. Expert Opin. Drug Metab. Toxicol.12(6), 633–644 (2016).
  • Li Shi-Yong , SunR, WangHXet 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. Release205, 7–14 (2015).
  • Habib JG , O'ShaughnessyJA. The hedgehog pathway in triple‐negative breast cancer. Cancer medicine5(10), 2989–3006 (2016).
  • Hamed AR , Abdel-AzimNS, ShamsKA, HammoudaFM. Targeting multidrug resistance in cancer by natural chemosensitizers. Bull. Natl Res. Cent.43, 8 (2019).
  • Dohse M , ScharenbergC, ShuklaSet al. Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab. Dispos.38(8), 1371–1380 (2010).
  • Shi Z , PengXX, KimIWet al. Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP binding cassette subfamily G member 2-mediated drug resistance. Cancer Res.67(22), 11012–11020 (2007).
  • Dai Cl , TiwariAK, WuCPet al. Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res.68(19), 7905–7914 (2008).
  • Tiwari AK , SodaniK, WangSRet al. Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem. Pharmacol.78(2), 153–161 (2009).
  • Sims JT , GangulySS, BennettH, FriendJW, TepeJ, PlattnerR. Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-kappaB and HSP27/p38/AKT pathways and by inhibiting ABCB1. PLoS ONE8(1), e55509 (2013).
  • Tabernero J , ShapiroGI, LorussoPMet al. First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov.3(4), 406–417 (2013).
  • Xie N , MouL, YuanJet al. Modulating drug resistance by targeting BCRP/ABCG2 using retrovirus-mediated RNA interference. PLoS ONE9(7), e103463(2014).
  • Hu J , LiJ, YueXet al. Targeting BCRP/ABCG2 by RNA interference enhances the chemotherapy sensitivity of human colon cancer side population cells. J. Huazhong Univ. Sci. Technol. Med. Sci.37, 231–236 (2017).
  • Su Z , LiuG, FangTet al. Silencing MRP1–4 genes by RNA interference enhances sensitivity of human hepatoma cells to chemotherapy. Am. J. Transl. Res8(6), 2790–2802 (2016).
  • Wang Y , ZhaoL, XiaoQet al. miR-302a/b/c/d cooperatively inhibit BCRP expression to increase drug sensitivity in breast cancer cells. Gynecol. Oncol.141( 3), 592–601 (2016).
  • Riddle RD , JohnsonRL, LauferE, TabinC. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell75(7), 1401–1416 (1993).
  • Dessaud E , McMahonAP, BriscoeJ. Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network. Development135(15), 2489–2503 (2008).
  • Machold R , HayashiS, RutlinMet al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron39(6), 937–950 (2003).
  • Bhardwaj G , MurdochB, WuDet al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat. Immunol.2(2), 172–180 (2001).
  • Skoda AM , SimovicD, KarinV, KardumV, VranicS, SermanL. The role of the Hedgehog signaling pathway in cancer: a comprehensive review. Bosn. J. Basic Med. Sci.18(1), 8–20 (2018).
  • Alexandre C , JacintoA, InghamPW. Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the cubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins. Genes Dev.10(16), 2003–2013 (1996).
  • Ruppert JM , KinzlerKW, WongAJet al. The GLI-Kruppel family of human genes. Mol. Cell. Biol.8(8), 3104–3113 (1988).
  • Sasaki H , NishizakiY, HuiC, NakafukuM, KondohH. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development126(17), 3915–3924 (1999).
  • Ramaswamy B , LuY, TengKet al. Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Res.72(19), 5048–5059 (2012).
  • Sun Y , WangY, FanCet al. Estrogen promotes stemness and invasiveness of ER-positive breast cancer cells through Gli1 activation. Mol. Cancer Ther.13, 137 (2014).
  • Thomas ZI , GibsonW, SextonJZet al. Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration. Br. J. Cancer104(10), 1575–1586 (2011).
  • Goel HL , PursellB, ChangCet al. GLI1 regulates a novel neuropilin-2/α6β1 integrin based autocrine pathway that contributes to breast cancer initiation. EMBO Mol. Med.5( 4), 488–508 (2013).
  • Harris LG , PannellLK, SinghS, SamantRS, ShevdeLA. Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of CYR61. Oncogene31(28), 3370–3380 (2012).
  • Colavito SA , ZouMR, YanQ, NguyenDX, SternDF. Significance of glioma-associated oncogene homolog 1 (GLI1) expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway. Breast Cancer Res. Treat.16(5), 444 (2014).
  • Johnson RW , NguyenMP, PadaleckiSSet al. TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res.71(3), 822–831 (2011).
  • Das S , SamantRS, ShevdeLA. Nonclassical activation of Hedgehog signaling enhances multidrug resistance and makes cancer cells refractory to Smoothened-targeting Hedgehog inhibition. J. Biol. Chem.288(17), 11824–11833 (2013).
  • O’Toole SA , MachalekDA, ShearerRFet al. Hedgehog overexpression is associated with stromal interactions and predicts for poor outcome in breast cancer. Cancer Res.71(11), 4002–4014 (2011).
  • Kwon YJ , HurstDR, StegADet al. Gli1 enhances migration and invasion via up-regulation of MMP-11 and promotes metastasis in ERα negative breast cancer cell lines. Clin. Exp. Metastasis28(5), 437–449 (2011).
  • Cao X , GeradtsJ, DewhirstMW, LoHW. Upregulation of VEGF-A and CD24 gene expression by the tGLI1 transcription factor contributes to the aggressive behavior of breast cancer cells. Oncogene31(1), 104–115 (2012).
  • Liu S , DontuG, MantleIDet al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res.66(12), 6063–6071 (2006).
  • Sims-Mourtada J , OpdenakerLM, DavisJ, ArnoldKM, FlynnD. Taxane-induced hedgehog signaling is linked to expansion of breast cancer stem-like populations after chemotherapy. Mol. Carcinog.54(11), 1480–1493 (2015).
  • Lei J , FanL, WeiGet al. Gli-1 is crucial for hypoxia-induced epithelial-mesenchymal transition and invasion of breast cancer. Tumour Biol.36(4), 3119–3126 (2015).
  • Arnold KM , PohligRT, Sims-MourtadaJ. Co-activation of Hedgehog and Wnt signaling pathways is associated with poor outcomes in triple negative breast cancer. Oncol. Lett.14(5), 5285–5292 (2017).
  • Han B , QuY, JinYet al. FOXC1 activates Smoothened-independent Hedgehog signaling in basal-like breast cancer. Cell Rep.13(5), 1046–1058 (2015).
  • Sekulic A , MigdenMR, OroAEet al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N. Engl. J. Med.366(23), 2171–2179 (2012).
  • Robinson GW , OrrBA, WuGet al. Vismodegib exerts targeted efficacy against recurrent sonic hedgehog-subgroup medulloblastoma: results from Phase II pediatric brain tumor consortium studies PBTC-025B and PBTC-032. J. Clin. Oncol.33(24), 2646–2654 (2015).
  • Bhateja P , CherianM, MajumderS, RamaswamyB. The Hedgehog signaling pathway: a viable target in breast cancer?Cancers (Basel)11(8), 1126 (2019).
  • Koike Y , OhtaY, SaitohWet al. Anti-cell growth and anti-cancer stem cell activities of the non-canonical hedgehog inhibitor GANT61 in triple-negative breast cancer cells. Breast Cancer Res. Treat.24(5), 683–693 (2017).
  • Clevers H , NusseR. Wnt/beta-catenin signaling and disease. Cell149(6), 1192–1205 (2012).
  • Staal FJ , LuisTC, TiemessenMM. WNT signalling in the immune system: WNT is spreading its wings. Nat. Rev. Immunol.8(8), 581–593 (2008).
  • Gieseck RL , WilsonMS, WynnTA. Type 2 immunity in tissue repair and fibrosis. Nat. Rev. Immunol.18(1), 62–76 (2018).
  • Ng LF , KaurP, BunnagNet al. WNT signaling in disease. Cells8(8), 826 (2019).
  • Khramtsov AI , KhramtsovaGF, TretiakovaM, HuoD, OlopadeOI, GossKH. Wnt/β-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am. J. Pathol.176(6), 2911–2920 (2010).
  • Geyer FC , Lacroix-TrikiM, SavageKet al. β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod. Pathol.24(2), 209–231 (2011).
  • Dey N , BarwickBG, MorenoCSet al. Wnt signaling in triple negative breast cancer is associated with metastasis. BMC Cancer13, 1 (2013).
  • Xu J , ProsperiJR, ChoudhuryN, OlopadeOI, GossKH. β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells. PLoS ONE10(2), e0117097(2015).
  • Borg J-P , BelottiE, DaulatAet al. Deregulation of the non-canonical pathway in triple-negative breast cancer. FASEB J.27, 610–611 (2013).
  • Shen H , YanW, YuanJ, WangZ, WangC. Nek2B activates the Wnt pathway and promotes triple-negative breast cancer chemothezrapy-resistance by stabilizing β-catenin. J. Exp. Clin. Cancer Res.38(1), 243 (2019).
  • Fultang N , ChakrabortyM, PeethambaranB. Regulation of cancer stem cells in triple negative breast cancer. Cancer Drug Resistance4(2), 321–342 (2021).
  • Gangrade A , PathakV, Augelli-SzafranCEet al. Preferential inhibition of Wnt/β-catenin signaling by novel benzimidazole compounds in triple-negative breast cancer. Int. J. Mol. Sci.19(5), 1524 (2018).
  • Gupta PB , OnderTT, JiangGet al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell138(4), 645–659 (2009).
  • Jang GB , HongIS, KimRJet al. Wnt/β-catenin small-molecule inhibitor CWP232228 preferentially inhibits the growth of breast cancer stem-like cells. Cancer Res.75(8), 1691–1702 (2015).
  • Johnson JP , KumarP, KoulnisM, PatelM, SiminK. Crucial and novel cancer drivers in a mouse model of triple-negative breast cancer. Cancer Genomics Proteomics11(3), 115–126 (2014).
  • Poulsen A , SooYH, WangWet al. Pharmacophore model for Wnt/Porcupine inhibitors and its use in drug design. J. Chem. Inf. Model.55(7), 1435–1448 (2015).
  • Langton PF , KakugawaS, VincentJP. Making, exporting, and modulating Wnts. Trends Cell Biol.26(10), 756–765 (2016).
  • Agarwal P , ZhangB, HoYet al. Enhanced targeting of CML stem and progenitor cells by inhibition of porcupine acyltransferase in combination with TKI. Blood129(8), 1008–1020 (2017).
  • Bhamra I , ArmerR, BinghamMet al. Porcupine inhibitor RXC004 enhances immune response in pre-clinical models of cancer. Cancer Res.78, Abstract 3764 (2018).
  • Valenta T , HausmannG, BaslerK. The many faces and functions of beta-catenin. EMBO J.31(12), 2714–2736 (2012).
  • Fan Y , DuttaJ, GuptaN, FanG, GélinasC. Regulation of programmed cell death by NF-κB and its role in tumorigenesis and therapy. Adv. Exp. Med. Biol.615, 223–250 (2008).
  • Gupta SC , KimJH, PrasadS, AggarwalBB. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metas. Rev.29(3), 405–434 (2010).
  • Td G . Multiple myeloma: lusting for NF-kappaB. Cancer Cell12(2), 95–97 (2007).
  • Ossovskaya V , WangY, BudoffAet al. Exploring molecular pathways of triple-negative breast cancer. Genes Cancer2(9), 870–879 (2011).
  • Fusella F , SeclìL, BussoEet al. The IKK/NF-κB signaling pathway requires Morgana to drive breast cancer metastasis. Nat. Commun.8(1), 1636 (2017).
  • Chaturvedi MM , SungB, YadavVR, KannappanR, AggarwalBB. NF-kappaB addiction and its role in cancer: ‘one size does not fit all’. Oncogene30(14), 1615–1630 (2011).
  • Hossain F , SorrentinoC, UcarDAet al. Notch signaling regulates mitochondrial metabolism and NF-κB activity in triple-negative breast cancer cells via IKKα-dependent non-canonical pathways. Front. Oncol.8, 575 (2018).
  • Kim T , YangS-J, HwangDet al. A basal-like breast cancer-specific role for SRF–IL6 in YAP-induced cancer stemness. Nat. Comm.6(1), 1–15 (2015).
  • Barbie TU , AlexeG, ArefARet al. Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth. J. Clin. Invest.124(12), 5411–5423 (2014).
  • Messeha SS , ZarmouhNO, MendoncaP, AlwagdaniH, KoltaMG, SolimanKFA. The inhibitory effects of plumbagin on the NF-κB pathway and CCL2 release in racially different triple-negative breast cancer cells. PLoS ONE13(7), 1–25 (2018).
  • Erkel G , AnkeT, SternerO. Inhibition of NF-κB activation by panepoxydone. Biochem. Biophys. Res. Commun.226(1), 214–221 (1996).
  • Pan H , ZhouW, HeWet al. 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 (2012).
  • Degraffenried LA , ChandrasekarB, FriedrichsWEet al. NF-kappa B inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen. Ann. Oncol.15(6), 885–890 (2004).
  • Aster JC , PearWS, BlacklowSC. The varied roles of Notch in cancer. Annu. Rev. Pathol. Mech. Dis.12, 245–275 (2017).
  • Ranganathan P , WeaverKL, CapobiancoAJ. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat. Rev. Cancer11(5), 338–351 (2011).
  • Takebe N , NguyenD, YangSX. Targeting notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol. Ther.141(2), 140–149 (2014).
  • Andersson ER , LendahlU. Therapeutic modulation of Notch signalling–are we there yet?Nat. Rev. Drug Discov.13(5), 357–378 (2014).
  • Takebe N , MieleL, HarrisPJet al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol.12(8), 445–464 (2015).
  • Espinoza I , MieleL. Notch inhibitors for cancer treatment. Pharmacol. Ther.139(2), 95–110 (2013).
  • Rustighi A , ZanniniA, TiberiLet al. Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast. EMBO Mol. Med.6(1), 99–119 (2014).
  • Harrison H , FarnieG, HowellSJet al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res.70(2), 709–718 (2010).
  • Weng AP , FerrandoAA, LeeW. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science306(5694), 269–271 (2004).
  • Wang K , ZhangQ, LiDet al. PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a gamma-secretase inhibitor. Clin. Cancer Res.21(6), 1487–1496 (2015).
  • Zhu H , BhaijeeF, IshaqNet al. Correlation of Notch1, pAKT and nuclear NF-kappaB expression in triple negative breast cancer. Am. J. Cancer Res.3(2), 230–239 (2013).
  • Pan H , ZhouW, HeWet al. 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 (2012).
  • Qiu M , PengQ, JiangIet al. Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells. Cancer Lett.328(2), 261–270 (2013).
  • Mittal S , SharmaA, BalajiSAet al. Coordinate hyperactivation of Notch1 and Ras/MAPK pathways correlates with poor patient survival: novel therapeutic strategy for aggressive breast cancers. Mol. Cancer Ther.13(12), 3198–3209 (2014).
  • Boelens MC , WuTJ, NabetBYet al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell159(3), 499–513 (2014).
  • Zhang X , LiuX, LuoJet al. Notch3 inhibits epithelial–mesenchymal transition by activating Kibra-mediated Hippo/YAP signaling in breast cancer epithelial cells. Oncogenesis5, e269 (2016).
  • Giuli MV , GiulianiE, ScrepantiI, BellaviaD, ChecquoloS. Notch signaling activation as a hallmark for triple-negative breast cancer subtype. Journal of oncology (2019).
  • Guo S , LiuM, Gonzalez-PerezRR. Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim. Biophys. Acta1815(2), 197–213 (2011).
  • Checquolo S , PalermoR, CialfiSet al. Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia. Oncogene29(10), 1463–1474 (2010).
  • Cialfi S , PalermoR, MancaSet al. Glucocorticoid sensitivity of T-cell lymphoblastic leukemia/lymphoma is associated with glucocorticoid receptor-mediated inhibition of Notch1 expression. Leukemia27(2), 485–488 (2013).
  • Franciosa G , DiluvioG, GaudioFDet al. Prolyl-isomerase Pin1 controls Notch3 protein expression and regulates T-ALL progression. Oncogene35(36), 4741–4751 (2016).
  • Locatelli MA , AftimosP, DeesECet al. Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer. Oncotarget8(2), 2320–2328 (2017).
  • Schott AF , LandisMD, DontuGet al. Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin. Cancer Res19(6), 1512–1524 (2013).
  • Broner EC , AlpertG, GluschnaiderUet al. AL101 mediated tumor inhibition in notch-altered TNBC PDX models. J. Clin. Oncol.37(Suppl. 15), Abstract 1064 ( 2019).
  • Smith DC , ChughR, PatnaikAet al. A Phase 1 dose escalation and expansion study of Tarextumab (OMP-59R5) in patients with solid tumors. Invest. New Drugs37( 4), 722–730 (2019).
  • Rosen LS , WesolowskiR, BaffaRet al. A Phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody–drug conjugate, in patients with breast cancer and other advanced solid tumors. Invest. New Drugs38(1), 120–130 (2019).
  • Camargo FD , GokhaleS, JohnnidisJBet al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol.17(23), 2054–2060 (2007).
  • Pan D . Hippo signaling in organ size control. Genes Dev.21(8), 886–897 (2007).
  • Vlug EJ , vande Ven RAH, VermeulenJF, BultP, Van DiestPJ, DerksenPWB. Nuclear localization of the transcriptional coactivator YAP is associated with invasive lobular breast cancer. Cell. Oncol.36(5), 375–384 (2013).
  • Kim HM , JungW, KooJS. Expression of Yes-associated protein (YAP) in metastatic breast cancer. Int. J. Clin. Exp. Pathol.8(9), 11248–11257 (2015).
  • Zhao Y , KhanalP, SavageP, SheYM, CyrTD, YangX. YAP-induced resistance of cancer cells to antitubulin drugs is modulated by a Hippo-independent pathway. Cancer Res.74(16), 4493–4503 (2014).
  • Sulaiman A , McGarryS, El-SahliSet al. Co-targeting bulk tumor and CSCs in clinically translatable TNBC patient-derived xenografts via combination nanotherapy. Mol. Cancer Ther.18(10), 1755–1764 (2019).
  • Zhao B , LiL, GuanKl. Hippo signalling at a glance. Cell Sci123(23), 4001–4006 (2010).
  • Barry ER , CamargoFD. The Hippo superhighway: signalling cross roads converging on the Hippo/Yap pathway in stem cells and development. Curr. Opin. Cell Biol.25(2), 247–253 (2013).
  • Varelas X . The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development141(8), 1614–1626 (2014).
  • Yu FX , MengZ, PlouffeSW, GuanKl. Hippo pathway regulation of gastrointestinal tissues. Annu. Rev. Physiol.77, 201–227 (2014).
  • Moroishi T , HansenCG, GuanKl. The emerging roles of YAP and TAZ in cancer. Nat. Rev. Cancer15(2), 73–79 (2015).
  • Piccolo S , DupontS, CordenonsiM. The biology of YAP/TAZ: Hippo signalling and beyond. Physiol. Rev.94(4), 1287–1312 (2014).
  • Atkins M , PotierD, RomanelliLet al. An ectopic network of transcription factors regulated by Hippo signaling drives growth and invasion of a malignant tumor model. Curr. Biol.26(16), 2101–2113 (2016).
  • Vici P , ErcolaniC, DiBenedetto Aet al. Topographic expression of the Hippo transducers TAZ and YAP in triple-negative breast cancer treated with neoadjuvant chemotherapy. J. Exp. Clin. Cancer Res.35, 62 (2016).
  • Maugeri-Saccà M , DeMaria R. Hippo pathway and breast cancer stem cells. Critical reviews in oncology/hematology. 99, 115–122 (2016).
  • Vuoriluoto K , HaugenH, KiviluotoSet al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene30(12), 1436–1448 (2011).
  • Virtakoivu R , MaiA, MattilaEet al. Vimentin–ERK signaling uncouples Slug gene regulatory function. Cancer Res.75(11), 2349–2362 (2015).
  • Song S , HonjoS, JinJet al. The Hippo coactivator YAP1 mediatesEGFR overexpression and confers chemoresistance in esophageal cancer. Clin. Cancer Res.21(11), 2580–2590 (2015).
  • Mao B , HuF, ChengJet al. SIRT1 regulates YAP2-mediated cell proliferation and chemoresistance in hepatocellular carcinoma. Oncogene33(11), 1468–1474 (2014).
  • Xia Y , ZhangYL, YuC, ChangT, FanHY. YAP/TEAD co-activator regulated pluripotency and chemoresistance in ovarian cancer initiated cells. PLoS ONE9(11), e109575 (2014).
  • Huo X , ZhangQ, LiuAMet al. Overexpression of Yes-associated protein confers doxorubicin resistance in hepatocellullar carcinoma. Oncol. Rep.29(2), 840–846 (2013).
  • Cheng H , ZhangZ, Rodriguez-BarruecoRet al. Functional genomics screen identifies YAP1 as a key determinant to enhance treatment sensitivity in lung cancer cells. Oncotarget7(20), 28976–28988 (2016).
  • Fernandez-L A , SquatritoM, NorthcottPet al. Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation. Oncogene31(15), 1923–1937 (2012).
  • Tsujiura M , MazackV, SudolMet al. Yes-associated protein (YAP) modulates oncogenic features and radiation sensitivity in endometrial cancer. PLoS ONE9(6), e100974 (2014).
  • Andrade D , MehtaM, GriffithJet al. YAP1 inhibition radiosensitizes triple negative breast cancer cells by targeting the DNA damage response and cell survival pathways. Oncotarget8(58), 98495 (2017).
  • Jiao S , WangH, ShiZet al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell25(2), 166–180 (2014).
  • Sorrentino G , RuggeriN, SpecchiaVet al. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat. Cell Biol.16(4), 357–366 (2014).
  • Wang C , ZhuX, FengWet al. Verteporfin inhibits YAP function through up-regulating 14-3-3σ sequestering YAP in the cytoplasm. Am. J. Cancer Res.6(1), 27–37 (2015).
  • Oku Y , NishiyaN, ShitoTet al. Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers. FEBS Open Bio5(1), 542–549 (2015).
  • Moroishi T , HayashiT, PanWWet al. The Hippo pathway kinases LATS1/2 suppress cancer immunity. Cell167(6), 1525.e1517–1539.e1517 (2016).
  • Mittendorf EA , PhilipsA, MericbernstamFet al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol. Res.2(4), 361–370 (2014).
  • Schmid P , CruzC, BraitehFSet al. Atezolizumab in metastatic TNBC (mTNBC): long-term clinical outcomes and biomarker analyses. Cancer Res.77(Suppl. 13), Abstract 2986 (2017).
  • Yang Y , LiX, WangT, GuoQ, XiT, ZhengL. Emerging agents that target signaling pathways in cancer stem cells. Journal of hematology & oncology13, 1–8 (2020).
  • Guanizo AC , FernandoCD, GaramaDJ, GoughDJ. STAT3: a multifaceted oncoprotein. Growth Factors36(1–2), 1–14 (2018).
  • Pollack V , SarkoziR, BankiZet al. Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling. Am. J. Physiol. Renal Physiol.293(5), F1714–F1726 (2007).
  • Junk DJ , BrysonBL, SmigielJM, ParameswaranN, BartelCA, JacksonMW. Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling. Oncogene36(28), 4001–4013 (2017).
  • Kucia-Tran JA , TulkkiV, SmithSet al. Overexpression of the oncostatin-M receptor in cervical squamous cell carcinoma is associated with epithelial mesenchymal transition and poor overall survival. Br. J. Cancer115(2), 212–222 (2016).
  • Smigiel JM , ParameswaranN, JacksonMW. Potent EMT and CSC phenotypes are induced by oncostatin-M in pancreatic cancer. Mol. Cancer Res.15(4), 478–488 (2017).
  • Yu ZJ , LiZ, WangCCet al. Oncostatin M receptor, positively regulated by SP1, promotes gastric cancer growth and metastasis upon treatment with Oncostatin M. Gastric Cancer22(5), 955–966 (2019).
  • Sirkisoon SR , CarpenterRL, RimkusTet al. Interaction between STAT3 and GLI1/tGLI1 oncogenic transcription factors promotes the aggressiveness of triple-negative breast cancers and HER2-enriched breast cancer. Oncogene37(19), 2502–2514 (2018).
  • Kuo WY , HwuL, WuCY, LeeJS, ChangCW, LiuRS. STAT3/NF-κB-regulated lentiviral TK/GCV suicide gene therapy for cisplatin-resistant triple-negative breast cancer. Theranostics7(3), 647–663 (2017).
  • Moreira MP , BragaL, CassaliGD, SilvaLM. STAT3 as a promising chemoresistance biomarker associated with the CD44+/high/CD24−/low/ALDH+ BCSCs-like subset of the triple-negative breast cancer (TNBC) cell line. Exp. Cell Res.363(2), 283–290 (2018).
  • Wang K , ZhuX, ZhangK, YinY, ChenY, ZhangT. Interleukin-6 contributes to chemoresistance in MDA-MB-231 cells via targeting HIF-1α. J. Biochem. Mol. Toxicol.32(3), 1–7 (2018).
  • Qin JJ , YanL, ZhangJ, ZhangWD. STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review. J. Exp. Clin. Cancer Res.38(1), 195 (2019).
  • Vyas D , Lopez-HisijosN, ShahPet al. A second-generation proteasome inhibitor and doxorubicin modulates IL-6, pSTAT-3 and NF-kB activity in MDA-MB-231 breast cancer cells. J. Nanosci. Nanotechnol.17(1), 175–185 (2017).
  • Tian J , ChenX, FuSet al. Bazedoxifene is a novel IL-6/GP130 inhibitor for treating triple-negative breast cancer. Breast Cancer Res. Treat.175(3), 553–566 (2019).
  • Fu S , ChenX, LoHW, LinJ. Combined bazedoxifene and paclitaxel treatments inhibit cell viability, cell migration, colony formation, and tumor growth and induce apoptosis in breast cancer. Cancer Lett.448, 11–19 (2019).
  • Aryappalli P , Al-QubaisiSS, AttoubSet al. The IL-6/STAT3 signaling pathway is an early target of Manuka honey induced suppression of human breast cancer cells. Front. Oncol.7, 167 (2017).
  • Rios-Fuller TJ , Ortiz-SotoG, Lacourt-VenturaMet al. Ganoderma lucidum extract (GLE) impairs breast cancer stem cells by targeting the STAT3 pathway. Oncotarget9(89), 35907–35921 (2018).
  • Kim S , JeonM, LeeJ et al. Induction of fibronectin in response to epidermal growth factor is suppressed by silibinin through the inhibition of STAT3 in triple negative breast cancer cells. Oncol. Rep.32(5), 2230–2236 (2014).
  • Mehta R , KattaH, AlimirahFet al. Deguelin action involves c-met and EGFR signaling pathways in triple negative breast cancer cells. PLoS ONE8(6), e65113 (2013).
  • Chun J , ParkM, KoH, LeeK, KimYS. Bioassay-guided isolation of cantharidin from blister beetles and its anticancer activity through inhibition of epidermal growth factor receptor-mediated STAT3 and Akt pathways. J. Nat. Med.72(4), 937–945 (2018).
  • Yamashita N , KondoM, ZhaoSet al. Picrasidine G decreases viability of MDA-MB 468 EGFR-overexpressing triple-negative breast cancer cells through inhibition of EGFR/STAT3 signaling pathway. Bioorg. Med. Chem. Lett.27(11), 2608–2612 (2017).
  • Kim HS , HoangVH, HongMet al. Investigation of B,C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors for use as anti-breast cancer agents. Bioorg. Med. Chem.27(7), 1370–1381 (2019).
  • Cho TM , KimJY, KimYJet al. C-terminal HSP90 inhibitor L80 elicits anti-metastatic effects in triple-negative breast cancer via STAT3 inhibition. Cancer Lett.447, 141–153 (2019).
  • Tegowski M , FanC, BaldwinAS. Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G1 arrest independent of DRD2. J. Biol. Chem.293(41), 15977–15990 (2018).
  • Cheng CC , ShiLH, WangXJet al. Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066. Int. J. Oncol.53, 339–348 (2018).
  • Chen Y , JiM, ZhangSet al. Bt354 as a new STAT3 signaling pathway inhibitor against triple negative breast cancer. J. Drug Target.26(10), 920–930 (2018).
  • Zhang W , YuW, CaiG et al. A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy. Cell Death Dis.9(11), 1098 (2018).

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