Skip to main content
SpringerLink
Log in

Notch Signaling and the Breast Cancer Microenvironment

  • Chapter
  • First Online:
Notch Signaling in Embryology and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1287))

Abstract

Notch promotes breast cancer progression through tumor initiating cell maintenance, tumor cell fate specification, proliferation, survival, and motility. In addition, Notch is recognized as a decisive mechanism in regulating various juxtacrine and paracrine communications in the tumor microenvironment (TME). In this chapter, we review recent studies on stress-mediated Notch activation within the TME and sequelae such as angiogenesis, extracellular matrix remodeling, changes in the innate and adaptive immunophenotype, and therapeutic perspectives.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ackerman D, Simon MC (2014) Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol 24(8):472–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Al-Hajj M et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ali HR et al (2014) Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol 25(8):1536–1543

    Article  CAS  PubMed  Google Scholar 

  • Ali HR et al (2016) Patterns of immune infiltration in breast cancer and their clinical implications: a gene-expression-based retrospective study. PLoS Med 13(12):e1002194

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Altieri DC (2008) Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8(1):61–70

    Article  CAS  PubMed  Google Scholar 

  • Anan K et al (1996) Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer. Surgery 119(3):333–339

    Article  CAS  PubMed  Google Scholar 

  • Annecke K et al (2008) uPA and PAI-1 in breast cancer: review of their clinical utility and current validation in the prospective NNBC-3 trial. Adv Clin Chem 45:31–45

    Article  CAS  PubMed  Google Scholar 

  • Argyle D, Kitamura T (2018) Targeting macrophage-recruiting chemokines as a novel therapeutic strategy to prevent the progression of solid tumors. Front Immunol 9:2629

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arnold A, Papanikolaou A (2005) Cyclin D1 in breast cancer pathogenesis. J Clin Oncol 23(18):4215–4224

    Article  CAS  PubMed  Google Scholar 

  • Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125(Pt 23):5591–5596

    Article  CAS  PubMed  Google Scholar 

  • Bane AL et al (2008) Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors. Breast Cancer Res Treat

    Google Scholar 

  • Bates GJ et al (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24(34):5373–5380

    Article  PubMed  Google Scholar 

  • Benne C et al (2009) Notch increases T/NK potential of human hematopoietic progenitors and inhibits B cell differentiation at a pro-B stage. Stem Cells 27(7):1676–1685

    Article  CAS  PubMed  Google Scholar 

  • Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432(7015):332–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Binnewies M et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24(5):541–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boelens MC et al (2014) Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159(3):499–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bowers AJ, Scully S, Boylan JF (2003) SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia. Oncogene 22(18):2823–2835

    Article  CAS  PubMed  Google Scholar 

  • Callahan R, Egan SE (2004) Notch signaling in mammary development and oncogenesis. J Mammary Gland Biol Neoplasia 9(2):145–163

    Article  PubMed  Google Scholar 

  • Callahan R, Raafat A (2001) Notch signaling in mammary gland tumorigenesis. J Mammary Gland Biol Neoplasia 6(1):23–36

    Article  CAS  PubMed  Google Scholar 

  • Carmeliet P (2005) VEGF as a key mediator of angiogenesis in cancer. Oncology 69 Suppl 3:4–10

    Article  PubMed  CAS  Google Scholar 

  • Chen JJ et al (2005) Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol 23(5):953–964

    Article  CAS  PubMed  Google Scholar 

  • Chen J et al (2010) Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br J Cancer 102(2):351–360

    Article  CAS  PubMed  Google Scholar 

  • Cho OH et al (2009) Notch regulates cytolytic effector function in CD8+ T cells. J Immunol 182(6):3380–3389

    Article  CAS  PubMed  Google Scholar 

  • Classen A, Lloberas J, Celada A (2009) Macrophage activation: classical versus alternative. Methods Mol Biol 531:29–43

    Article  CAS  PubMed  Google Scholar 

  • Cohen B et al (2010) Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer. Breast Cancer Res Treat 123(1):113–124

    Article  CAS  PubMed  Google Scholar 

  • De Palma M (2016) Origins of brain tumor macrophages. Cancer Cell 30(6):832–833

    Article  PubMed  CAS  Google Scholar 

  • De Wever O et al (2004) Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J 18(9):1016–1018

    Article  PubMed  CAS  Google Scholar 

  • Denkert C et al (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28(1):105–113

    Article  CAS  PubMed  Google Scholar 

  • Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25(1):9–34

    Article  CAS  PubMed  Google Scholar 

  • Dickson BC et al (2007) High-level JAG1 mRNA and protein predict poor outcome in breast cancer. Mod Pathol 20(6):685–693

    Article  CAS  PubMed  Google Scholar 

  • Dieci MV et al (2018) Immune characterization of breast cancer metastases: prognostic implications. Breast Cancer Res 20(1):62

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Discher DE, Mooney DJ, Zandstra PW (2009) Growth factors, matrices, and forces combine and control stem cells. Science 324(5935):1673–1677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dontu G et al (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17(10):1253–1270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dontu G et al (2004) Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 6(6):R605–R615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du K, Ding J (2009) Insulin regulates TRB3 and other stress-responsive gene expression through induction of C/EBPbeta. Mol Endocrinol 23(4):475–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dupont S et al (2009) FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell 136(1):123–135

    Article  CAS  PubMed  Google Scholar 

  • Dvorak HF et al (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5):1029–1039

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dvorak KM et al (2018) Carcinoma associated fibroblasts (CAFs) promote breast cancer motility by suppressing mammalian Diaphanous-related formin-2 (mDia2). PLoS One 13(3):e0195278

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Edwards JP et al (2006) Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 80(6):1298–1307

    Article  CAS  PubMed  Google Scholar 

  • Esquivel-Velazquez M et al (2015) The role of cytokines in breast cancer development and progression. J Interf Cytokine Res 35(1):1–16

    Article  CAS  Google Scholar 

  • Farnie G et al (2007) Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. J Natl Cancer Inst 99(8):616–627

    Article  CAS  PubMed  Google Scholar 

  • Ferlay J et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386

    Article  CAS  PubMed  Google Scholar 

  • Foldi J et al (2016) RBP-J is required for M2 macrophage polarization in response to chitin and mediates expression of a subset of M2 genes. Protein Cell 7(3):201–209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foltz DR et al (2002) Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol 12(12):1006–1011

    Article  CAS  PubMed  Google Scholar 

  • Franchi L et al (2009) The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 10(3):241–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franklin RA et al (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344(6186):921–925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fryer CJ, White JB, Jones KA (2004) Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell 16(4):509–520

    Article  CAS  PubMed  Google Scholar 

  • Funahashi Y et al (2010) Notch regulates the angiogenic response via induction of VEGFR-1. J Angiogenes Res 2(1):3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fung E et al (2007) Delta-like 4 induces notch signaling in macrophages: implications for inflammation. Circulation 115(23):2948–2956

    Article  CAS  PubMed  Google Scholar 

  • Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gallahan D, Callahan R (1987) Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors. J Virol 61(1):66–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gallahan D, Kozak C, Callahan R (1987) A new common integration region (int-3) for mouse mammary tumor virus on mouse chromosome 17. J Virol 61(1):218–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gautier EL et al (2007) Enhanced immune system activation and arterial inflammation accelerates atherosclerosis in lupus-prone mice. Arterioscler Thromb Vasc Biol 27(7):1625–1631

    Article  CAS  PubMed  Google Scholar 

  • Giannoni E et al (2010) Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res 70(17):6945–6956

    Article  CAS  PubMed  Google Scholar 

  • Ginestier C et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gridley T (2007) Notch signaling in vascular development and physiology. Development 134(15):2709–2718

    Article  CAS  PubMed  Google Scholar 

  • Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guerriero JL (2018) Macrophages: the road less traveled, changing anticancer therapy. Trends Mol Med 24(5):472–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21(3):309–322

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Harrington LS et al (2008) Regulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells. Microvasc Res 75(2):144–154

    Article  CAS  PubMed  Google Scholar 

  • Harris DR, Mims A, Bunz F (2012) Genetic disruption of USP9X sensitizes colorectal cancer cells to 5-fluorouracil. Cancer Biol Ther 13(13):1319–1324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hashizume H et al (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156(4):1363–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoeben A et al (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56(4):549–580

    Article  CAS  PubMed  Google Scholar 

  • Houthuijzen JM, Jonkers J (2018) Cancer-associated fibroblasts as key regulators of the breast cancer tumor microenvironment. Cancer Metastasis Rev 37(4):577–597

    Article  CAS  PubMed  Google Scholar 

  • Hu C et al (2006) Overexpression of activated murine Notch1 and Notch3 in transgenic mice blocks mammary gland development and induces mammary tumors. Am J Pathol 168(3):973–990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu X et al (2008) Integrated regulation of Toll-like receptor responses by Notch and interferon-gamma pathways. Immunity 29(5):691–703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hua F et al (2011) TRB3 interacts with SMAD3 promoting tumor cell migration and invasion. J Cell Sci 124(Pt 19):3235–3246

    Article  CAS  PubMed  Google Scholar 

  • Huang SP et al (2004) Interleukin-6 increases vascular endothelial growth factor and angiogenesis in gastric carcinoma. J Biomed Sci 11(4):517–527

    Article  CAS  PubMed  Google Scholar 

  • Huang Y et al (2011) Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer Res 71(19):6122–6131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itoh M et al (2003) Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev Cell 4(1):67–82

    Article  CAS  PubMed  Google Scholar 

  • Izrailit J, Reedijk M (2012) Developmental pathways in breast cancer and breast tumor-initiating cells: therapeutic implications. Cancer Lett 317(2):115–126

    Article  CAS  PubMed  Google Scholar 

  • Izrailit J et al (2013) High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFbeta pathways as fundamental Notch regulators in breast cancer. Proc Natl Acad Sci U S A 110(5):1714–1719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Izrailit J et al (2017) Cellular stress induces TRB3/USP9x-dependent Notch activation in cancer. Oncogene 36(8):1048–1057

    Article  CAS  PubMed  Google Scholar 

  • Jablonska-Trypuc A, Matejczyk M, Rosochacki S (2016) Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem 31(sup1):177–183

    Article  CAS  PubMed  Google Scholar 

  • Jehn BM et al (2002) c-Cbl binding and ubiquitin-dependent lysosomal degradation of membrane-associated Notch1. J Biol Chem 277(10):8033–8040

    Article  CAS  PubMed  Google Scholar 

  • Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6(5):392–401

    Article  CAS  PubMed  Google Scholar 

  • Kiaris H et al (2004) Modulation of notch signaling elicits signature tumors and inhibits hras1-induced oncogenesis in the mouse mammary epithelium. Am J Pathol 165(2):695–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kyoizumi S et al (2017) Fate decision between group 3 innate lymphoid and conventional NK cell lineages by notch signaling in human circulating hematopoietic progenitors. J Immunol 199(8):2777–2793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee SH et al (2007) Mutational analysis of NOTCH1, 2, 3 and 4 genes in common solid cancers and acute leukemias. APMIS 115(12):1357–1363

    Article  CAS  PubMed  Google Scholar 

  • Lee CW et al (2008a) A functional Notch-survivin gene signature in basal breast cancer. Breast Cancer Res 10(6):R97

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee CW et al (2008b) Molecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis. Cancer Res 68(13):5273–5281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leibovich SJ et al (1987) Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature 329(6140):630–632

    Article  CAS  PubMed  Google Scholar 

  • Leong KG et al (2007) Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med 204(12):2935–2948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li L et al (2014) Notch-1 signaling promotes the malignant features of human breast cancer through NF-kappaB activation. PLoS One 9(4):e95912

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu H et al (2017) Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients. Breast Cancer Res Treat 166(1):95–107

    Article  CAS  PubMed  Google Scholar 

  • Liu Z et al (2018) TGF-beta1 secreted by M2 phenotype macrophages enhances the stemness and migration of glioma cells via the SMAD2/3 signalling pathway. Int J Mol Med 42(6):3395–3403

    CAS  PubMed  PubMed Central  Google Scholar 

  • Locatelli M, Curigliano G (2017) Notch inhibitors and their role in the treatment of triple negative breast cancer: promises and failures. Curr Opin Oncol 29(6):411–427

    Article  CAS  PubMed  Google Scholar 

  • Lu P et al (2011) Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 3(12)

    Google Scholar 

  • Lupo G et al (2016) Anti-angiogenic therapy in cancer: downsides and new pivots for precision medicine. Front Pharmacol 7:519

    PubMed  Google Scholar 

  • Mahmoud SM et al (2011) Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 29(15):1949–1955

    Article  PubMed  Google Scholar 

  • Mahmoud SM et al (2012) Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol 65(2):159–163

    Article  CAS  PubMed  Google Scholar 

  • Mantovani A et al (2008) Cancer-related inflammation. Nature 454(7203):436–444

    Article  CAS  PubMed  Google Scholar 

  • Mao L et al (2018) gamma-Secretase inhibitor reduces immunosuppressive cells and enhances tumour immunity in head and neck squamous cell carcinoma. Int J Cancer 142(5):999–1009

    Article  CAS  PubMed  Google Scholar 

  • Martin TA et al (2005) Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol 12(6):488–496

    Article  PubMed  Google Scholar 

  • Mathieu M et al (2013) Notch signaling regulates PD-1 expression during CD8(+) T-cell activation. Immunol Cell Biol 91(1):82–88

    Article  CAS  PubMed  Google Scholar 

  • McCann KE, Hurvitz SA, McAndrew N (2019) Advances in targeted therapies for triple-negative breast Cancer. Drugs 79(11):1217–1230

    Article  PubMed  Google Scholar 

  • McGill MA, McGlade CJ (2003) Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain. J Biol Chem 278(25):23196–23203

    Article  CAS  PubMed  Google Scholar 

  • Medrek C et al (2012) The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer 12:306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meurette O et al (2009) Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells. Cancer Res 69(12):5015–5022

    Article  CAS  PubMed  Google Scholar 

  • Miyoshi N et al (2009) Abnormal expression of TRIB3 in colorectal cancer: a novel marker for prognosis. Br J Cancer 101(10):1664–1670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mollen EWJ et al (2018) Moving breast cancer therapy up a notch. Front Oncol 8:518

    Article  PubMed  PubMed Central  Google Scholar 

  • Morikawa S et al (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160(3):985–1000

    Article  PubMed  PubMed Central  Google Scholar 

  • Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Movahedi K et al (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70(14):5728–5739

    Article  CAS  PubMed  Google Scholar 

  • Mukherjee A et al (2005) Regulation of Notch signalling by non-visual beta-arrestin. Nat Cell Biol 7(12):1191–1201

    Article  PubMed  CAS  Google Scholar 

  • Nichols JT, Miyamoto A, Weinmaster G (2007) Notch signaling–constantly on the move. Traffic 8(8):959–969

    Article  CAS  PubMed  Google Scholar 

  • Noguera-Troise I et al (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444(7122):1032–1037

    Article  CAS  PubMed  Google Scholar 

  • Noonan DM et al (2008) Inflammation, inflammatory cells and angiogenesis: decisions and indecisions. Cancer Metastasis Rev 27(1):31–40

    Article  PubMed  Google Scholar 

  • Ntziachristos P et al (2014) From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell 25(3):318–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oberg C et al (2001) The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog. J Biol Chem 276(38):35847–35853

    Article  CAS  PubMed  Google Scholar 

  • Ohoka N et al (2005) TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 24(6):1243–1255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ord D, Meerits K, Ord T (2007) TRB3 protects cells against the growth inhibitory and cytotoxic effect of ATF4. Exp Cell Res 313(16):3556–3567

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Osipo C et al (2008) ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a gamma-secretase inhibitor. Oncogene 27(37):5019–5032

    Article  CAS  PubMed  Google Scholar 

  • Outtz HH et al (2010) Notch1 deficiency results in decreased inflammation during wound healing and regulates vascular endothelial growth factor receptor-1 and inflammatory cytokine expression in macrophages. J Immunol 185(7):4363–4373

    Article  PubMed  CAS  Google Scholar 

  • Outtz HH et al (2011) Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood 118(12):3436–3439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palaga T et al (2008) Notch signaling is activated by TLR stimulation and regulates macrophage functions. Eur J Immunol 38(1):174–183

    Article  CAS  PubMed  Google Scholar 

  • Parr C, Watkins G, Jiang WG (2004) The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Int J Mol Med 14(5):779–786

    CAS  PubMed  Google Scholar 

  • Pietras K, Ostman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316(8):1324–1331

    Article  CAS  PubMed  Google Scholar 

  • Piulats J, Mitjans F (2008) Angiogenesis switch pathways. In: Bronchud MH et al (eds) Principles of molecular oncology, 3rd edn. Humana Press, Totowa, NJ, pp 239–256

    Chapter  Google Scholar 

  • Poltavets V et al (2018) The role of the extracellular matrix and its molecular and cellular regulators in cancer cell plasticity. Front Oncol 8:431

    Article  PubMed  PubMed Central  Google Scholar 

  • Polyak K (2011) Heterogeneity in breast cancer. J Clin Invest 121(10):3786–3788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ponti D et al (2005) Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 65(13):5506–5511

    Article  CAS  PubMed  Google Scholar 

  • Qi L et al (2006) TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312(5781):1763–1766

    Article  CAS  PubMed  Google Scholar 

  • Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu H et al (2018) Inhibiting Notch1 enhances immunotherapy efficacy in melanoma by preventing Notch1 dependent immune suppressive properties. Cancer Lett 434:144–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Radtke F, MacDonald HR, Tacchini-Cottier F (2013) Regulation of innate and adaptive immunity by Notch. Nat Rev Immunol 13(6):427–437

    Article  CAS  PubMed  Google Scholar 

  • Reedijk M (2012) Notch signaling and breast cancer. Adv Exp Med Biol 727:241–257

    Article  CAS  PubMed  Google Scholar 

  • Reedijk M et al (2005) High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 65(18):8530–8537

    Article  CAS  PubMed  Google Scholar 

  • Reedijk M et al (2008) JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer. Breast Cancer Res Treat 111(3):439–448

    Article  CAS  PubMed  Google Scholar 

  • Ren Y et al (2018) Paracrine and epigenetic control of CAF-induced metastasis: the role of HOTAIR stimulated by TGF-ss1 secretion. Mol Cancer 17(1):5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rizzo P et al (2008) Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res 68(13):5226–5235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roca C, Adams RH (2007) Regulation of vascular morphogenesis by Notch signaling. Genes Dev 21(20):2511–2524

    Article  CAS  PubMed  Google Scholar 

  • Rodemann HP, Muller GA (1991) Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. Am J Kidney Dis 17(6):684–686

    Article  CAS  PubMed  Google Scholar 

  • Roszer T (2015) Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediat Inflamm 2015:816460

    Article  CAS  Google Scholar 

  • Rustighi A et al (2009) The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nat Cell Biol 11(2):133–142

    Article  CAS  PubMed  Google Scholar 

  • Sansone P et al (2007a) p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells 25(3):807–815

    Article  CAS  PubMed  Google Scholar 

  • Sansone P et al (2007b) IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117(12):3988–4002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sappino AP et al (1988) Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues. Int J Cancer 41(5):707–712

    Article  CAS  PubMed  Google Scholar 

  • Schwarzer R et al (2006) TRB3 is a PI 3-kinase dependent indicator for nutrient starvation. Cell Signal 18(6):899–909

    Article  CAS  PubMed  Google Scholar 

  • Serini G, Gabbiani G (1999) Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 250(2):273–283

    Article  CAS  PubMed  Google Scholar 

  • Sethi N et al (2011) Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19(2):192–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shawber CJ et al (2007) Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest 117(11):3369–3382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen Q et al (2017) Notch shapes the innate immunophenotype in breast cancer. Cancer Discov 7(11):1320–1335

    Article  CAS  PubMed  Google Scholar 

  • Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12):1501–1512

    Article  CAS  PubMed  Google Scholar 

  • Shimizu M et al (2011) Plasminogen activator uPA is a direct transcriptional target of the JAG1-Notch receptor signaling pathway in breast cancer. Cancer Res 71(1):277–286

    Article  CAS  PubMed  Google Scholar 

  • Shimoda M, Mellody KT, Orimo A (2010) Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol 21(1):19–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siekmann AF, Lawson ND (2007) Notch signalling and the regulation of angiogenesis. Cell Adhes Migr 1(2):104–106

    Article  Google Scholar 

  • Sierra-Filardi E et al (2014) CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile. J Immunol 192(8):3858–3867

    Article  CAS  PubMed  Google Scholar 

  • Society AC. Cancer facts & figures 2015

    Google Scholar 

  • Sorlie T et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98(19):10869–10874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Studebaker AW et al (2008) Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Res 68(21):9087–9095

    Article  CAS  PubMed  Google Scholar 

  • Suchting S et al (2007) The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci U S A 104(9):3225–3230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugimoto K et al (2010) Notch2 signaling is required for potent antitumor immunity in vivo. J Immunol 184(9):4673–4678

    Article  CAS  PubMed  Google Scholar 

  • Svensson S et al (2015) CCL2 and CCL5 are novel therapeutic targets for estrogen-dependent breast cancer. Clin Cancer Res 21(16):3794–3805

    Article  CAS  PubMed  Google Scholar 

  • Takebe N et al (2015) Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12(8):445–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tattersall IW et al (2016) In vitro modeling of endothelial interaction with macrophages and pericytes demonstrates Notch signaling function in the vascular microenvironment. Angiogenesis 19(2):201–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor KL, Henderson AM, Hughes CC (2002) Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvasc Res 64(3):372–383

    Article  CAS  PubMed  Google Scholar 

  • Timmerman LA et al (2004) Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18(1):99–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuyada A et al (2012) CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res 72(11):2768–2779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vermeulen L et al (2010) Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12(5):468–476

    Article  CAS  PubMed  Google Scholar 

  • Vidula N, Bardia A (2017) Targeted therapy for metastatic triple negative breast cancer: the next frontier in precision oncology. Oncotarget 8(63):106167–106168

    Article  PubMed  PubMed Central  Google Scholar 

  • Vincent-Salomon A, Thiery JP (2003) Host microenvironment in breast cancer development: epithelial-mesenchymal transition in breast cancer development. Breast Cancer Res 5(2):101–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vonderheide RH, Domchek SM, Clark AS (2017) Immunotherapy for breast cancer: what are we missing? Clin Cancer Res 23(11):2640–2646

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang YC et al (2010) Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res 70(12):4840–4849

    Article  CAS  PubMed  Google Scholar 

  • Wang Y et al (2015) Elevated expression of USP9X correlates with poor prognosis in human non-small cell lung cancer. J Thorac Dis 7(4):672–679

    PubMed  PubMed Central  Google Scholar 

  • Wang M et al (2017) Mechanism of immune evasion in breast cancer. Onco Targets Ther 10:1561–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe MA et al (2010) Regulatory T cells and breast cancer: implications for immunopathogenesis. Cancer Metastasis Rev 29(4):569–579

    Article  CAS  PubMed  Google Scholar 

  • Weijzen S et al (2002) Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 8(9):979–986

    Article  CAS  PubMed  Google Scholar 

  • Wellenstein MD, de Visser KE (2018) Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape. Immunity 48(3):399–416

    Article  CAS  PubMed  Google Scholar 

  • Weng AP et al (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306(5694):269–271

    Article  CAS  PubMed  Google Scholar 

  • Wennemers M et al (2011) Tribbles homolog 3 denotes a poor prognosis in breast cancer and is involved in hypoxia response. Breast Cancer Res 13(4):R82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie Y et al (2013) Deubiquitinase FAM/USP9X interacts with the E3 ubiquitin ligase SMURF1 protein and protects it from ligase activity-dependent self-degradation. J Biol Chem 288(5):2976–2985

    Article  CAS  PubMed  Google Scholar 

  • Xu H et al (2012) Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat Immunol 13(7):642–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu J et al (2015) NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J Clin Invest 125(4):1579–1590

    Article  PubMed  PubMed Central  Google Scholar 

  • Xue J et al (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40(2):274–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi N et al (2008) NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer Res 68(6):1881–1888

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Zhang Y (2017) Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol 10(1):58

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yu W, Wang Y, Guo P (2018) Notch signaling pathway dampens tumor-infiltrating CD8(+) T cells activity in patients with colorectal carcinoma. Biomed Pharmacother 97:535–542

    Article  CAS  PubMed  Google Scholar 

  • Yuan X et al (2015) Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett 369(1):20–27

    Article  CAS  PubMed  Google Scholar 

  • Zeng Q et al (2005) Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8(1):13–23

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Edwards JP, Mosser DM (2006) Dynamic and transient remodeling of the macrophage IL-10 promoter during transcription. J Immunol 177(2):1282–1288

    Article  CAS  PubMed  Google Scholar 

  • Zheng S et al (2016) Inhibition of Notch signaling attenuates schistosomiasis hepatic fibrosis via blocking macrophage M2 polarization. PLoS One 11(11):e0166808

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou M et al (2015) Targeting of the deubiquitinase USP9X attenuates B-cell acute lymphoblastic leukemia cell survival and overcomes glucocorticoid resistance. Biochem Biophys Res Commun 459(2):333–339

    Article  CAS  PubMed  Google Scholar 

  • Zhou J et al (2016) Notch and TGFbeta form a positive regulatory loop and regulate EMT in epithelial ovarian cancer cells. Cell Signal 28(8):838–849

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Qiang Shen & Michael Reedijk

Authors
  1. Qiang Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Reedijk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Reedijk .

Editor information

Editors and Affiliations

  1. Department of Dermatology, Saarland University Medical Center, Homburg, Saarland, Germany

    Jörg Reichrath

  2. Department of Dermatology, Saarland University Medical Center, Homburg, Saarland, Germany

    Sandra Reichrath

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Shen, Q., Reedijk, M. (2021). Notch Signaling and the Breast Cancer Microenvironment. In: Reichrath, J., Reichrath, S. (eds) Notch Signaling in Embryology and Cancer. Advances in Experimental Medicine and Biology, vol 1287. Springer, Cham. https://doi.org/10.1007/978-3-030-55031-8_12

Download citation

Publish with us

Policies and ethics

Search

Navigation