Abstract
The interaction of breast epithelial cells with the surrounding extracellular matrix (ECM) is known to play a pivotal role during normal mammary gland development and function. It is also critical during the pathological changes that lead to breast cancer initiation and progression. A bidirectional crosstalk emerges upon interactions of epithelial cells with the ECM, which eventually dictates the genotypic and phenotypic programs that define normal gland function. Consequently, disruption of this communication contributes to the development of malignant phenotypes, which illustrate the process of breast cancer progression. The Discoidin Domain Receptors (DDRs) are collagen-binding receptor tyrosine kinases that are emerging as key mediators of cell−collagen interactions in breast tissues. DDRs signal in response to both basement membrane and interstitial collagens and thus they are well positioned to activate matrix-induced cellular programs during normal mammary gland development and function, and during dissemination of breast cancer cells. This chapter summarizes the current knowledge on the expression and function of DDRs in breast epithelial cells and their potential involvement in physiological and malignant processes. We also discuss the current challenges in understanding DDR expression and function in breast cancer tissues and experimental models and their potential as therapeutic targets.
Rodrigo Fernandez-Valdivia and Rafael Fridman are cosenior authors
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Fu HL et al (2013) Discoidin domain receptors: unique receptor tyrosine kinases in collagen-mediated signaling. J Biol Chem 288(11):7430–7437
Inman JL et al (2015) Mammary gland development: cell fate specification, stem cells and the microenvironment. Development 142(6):1028–1042
Sternlicht MD (2006) Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis. Breast Cancer Res 8(1):201
Oskarsson T (2013) Extracellular matrix components in breast cancer progression and metastasis. Breast 22(Suppl 2):S66–S72
Muschler J, Streuli CH (2010) Cell-matrix interactions in mammary gland development and breast cancer. Cold Spring Harb Perspect Biol 2(10):a003202
Obr AE et al (2013) Progesterone receptor and Stat5 signaling cross talk through RANKL in mammary epithelial cells. Mol Endocrinol 27(11):1808–1824
Fernandez-Valdivia R, Lydon JP (2012) From the ranks of mammary progesterone mediators, RANKL takes the spotlight. Mol Cell Endocrinol 357(1-2):91–100
Fernandez-Valdivia R et al (2005) Revealing progesterone’s role in uterine and mammary gland biology: insights from the mouse. Semin Reprod Med 23(1):22–37
Wiseman BS, Werb Z (2002) Stromal effects on mammary gland development and breast cancer. Science 296(5570):1046–1049
Sakakura T, Suzuki Y, Shiurba R (2013) Mammary stroma in development and carcinogenesis. J Mammary Gland Biol Neoplasia 18(2):189–197
Lambert AW, Ozturk S, Thiagalingam S (2012) Integrin signaling in mammary epithelial cells and breast cancer. ISRN Oncol 2012:493283
Schedin P, Keely PJ (2011) Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harb Perspect Biol 3(1):a003228
Brownfield DG et al (2013) Patterned collagen fibers orient branching mammary epithelium through distinct signaling modules. Curr Biol 23(8):703–709
Ingman WV et al (2006) Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev Dyn 235(12):3222–3229
Rodriguez D, Morrison CJ, Overall CM (2010) Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Biochim Biophys Acta 1803(1):39–54
Faraci-Orf E, McFadden C, Vogel WF (2006) DDR1 signaling is essential to sustain Stat5 function during lactogenesis. J Cell Biochem 97(1):109–121
Vogel WF et al (2001) Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development. Mol Cell Biol 21(8):2906–2917
Cellurale C et al (2012) Role of JNK in mammary gland development and breast cancer. Cancer Res 72(2):472–481
Crowley MR, Bowtell D, Serra R (2005) TGF-beta, c-Cbl, and PDGFR-alpha the in mammary stroma. Dev Biol 279(1):58–72
Joseph H et al (1999) Overexpression of a kinase-deficient transforming growth factor-beta type II receptor in mouse mammary stroma results in increased epithelial branching. Mol Biol Cell 10(4):1221–1234
Roarty K, Serra R (2007) Wnt5a is required for proper mammary gland development and TGF-beta-mediated inhibition of ductal growth. Development 134(21):3929–3939
Fernandez-Valdivia R et al (2008) Transcriptional response of the murine mammary gland to acute progesterone exposure. Endocrinology 149(12):6236–6250
Brisken C et al (1999) Prolactin controls mammary gland development via direct and indirect mechanisms. Dev Biol 210(1):96–106
Cui Y et al (2004) Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol 24(18):8037–8047
Miyoshi K et al (2001) Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium. J Cell Biol 155(4):531–542
Mukherjee A et al (2010) Targeting RANKL to a specific subset of murine mammary epithelial cells induces ordered branching morphogenesis and alveologenesis in the absence of progesterone receptor expression. FASEB J 24(11):4408–4419
Santos SJ, Haslam SZ, Conrad SE (2010) Signal transducer and activator of transcription 5a mediates mammary ductal branching and proliferation in the nulliparous mouse. Endocrinology 151(6):2876–2885
Fata JE et al (2000) The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103(1):41–50
Rayala SK et al (2006) Essential role of KIBRA in co-activator function of dynein light chain 1 in mammalian cells. J Biol Chem 281(28):19092–19099
Harris J et al (2006) Socs2 and elf5 mediate prolactin-induced mammary gland development. Mol Endocrinol 20(5):1177–1187
Hilton HN et al (2008) KIBRA interacts with discoidin domain receptor 1 to modulate collagen-induced signalling. Biochim Biophys Acta 1783(3):383–393
Chen J et al (2002) The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 161(1):337–344
Gardner H et al (1996) Deletion of integrin alpha 1 by homologous recombination permits normal murine development but gives rise to a specific deficit in cell adhesion. Dev Biol 175(2):301–313
Spike BT et al (2012) A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer. Cell Stem Cell 10(2):183–197
Wansbury O et al (2011) Transcriptome analysis of embryonic mammary cells reveals insights into mammary lineage establishment. Breast Cancer Res 13(4):R79
Bai L, Rohrschneider LR (2010) s-SHIP promoter expression marks activated stem cells in developing mouse mammary tissue. Genes Dev 24(17):1882–1892
Shackleton M et al (2006) Generation of a functional mammary gland from a single stem cell. Nature 439(7072):84–88
Kano K et al (2008) A novel dwarfism with gonadal dysfunction due to loss-of-function allele of the collagen receptor gene, Ddr2, in the mouse. Mol Endocrinol 22(8):1866–1880
Labrador JP et al (2001) The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO Rep 2(5):446–452
Cowling RT et al (2014) Discoidin domain receptor 2 germline gene deletion leads to altered heart structure and function in the mouse. Am J Physiol Heart Circ Physiol 307(5):H773–H781
Zhang K et al (2013) The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat Cell Biol 15(6):677–687
Dontu G et al (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17(10):1253–1270
Huang S et al (2005) Changes in gene expression during the development of mammary tumors in MMTV-Wnt-1 transgenic mice. Genome Biol 6(10):R84
Li Y et al (2003) Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci U S A 100(26):15853–15858
Rosen PP (2009) Rosen’s breast pathology, 3rd edn. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, p 1116
Elledge RM et al (1998) HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group Study. Clin Cancer Res 4(1):7–12
Osborne CK (1998) Tamoxifen in the treatment of breast cancer. N Engl J Med 339(22):1609–1618
Slamon D, Pegram M (2001) Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin Oncol 28(1 Suppl 3):13–19
Perou CM et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752
Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70
Burstein MD et al (2015) Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res 21(7):1688–1698
Maskarinec G et al (2013) Mammographic density as a predictor of breast cancer survival: the Multiethnic Cohort. Breast Cancer Res 15(1):R7
Tice JA et al (2013) Benign breast disease, mammographic breast density, and the risk of breast cancer. J Natl Cancer Inst 105(14):1043–1049
Ursin G et al (2005) Greatly increased occurrence of breast cancers in areas of mammographically dense tissue. Breast Cancer Res 7(5):R605–R608
Boyd NF et al (2001) Mammographic density as a marker of susceptibility to breast cancer: a hypothesis. IARC Sci Publ 154:163–169
Martin LJ, Boyd NF (2008) Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. Breast Cancer Res 10(1):201
Paszek MJ et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8(3):241–254
Provenzano PP, Eliceiri KW, Keely PJ (2009) Shining new light on 3D cell motility and the metastatic process. Trends Cell Biol 19(11):638–648
Provenzano PP et al (2006) Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med 4(1):38
Valiathan RR et al (2012) Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev 31(1-2):295–321
Vogel W et al (1997) The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1(1):13–23
Toy KA et al (2015) Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer. Breast Cancer Res Treat 150(1):9–18
Yeh YC, Wang CZ, Tang MJ (2009) Discoidin domain receptor 1 activation suppresses alpha2beta1 integrin-dependent cell spreading through inhibition of Cdc42 activity. J Cell Physiol 218(1):146–156
Ren T et al (2013) Increased expression of discoidin domain receptor 2 (DDR2): a novel independent prognostic marker of worse outcome in breast cancer patients. Med Oncol 30(1):397
Dejmek J et al (2003) Wnt-5a and G-protein signaling are required for collagen-induced DDR1 receptor activation and normal mammary cell adhesion. Int J Cancer 103(3):344–351
Turashvili G et al (2007) Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer 7:55
Wang CZ, Yeh YC, Tang MJ (2009) DDR1/E-cadherin complex regulates the activation of DDR1 and cell spreading. Am J Physiol Cell Physiol 297(2):C419–C429
Eswaramoorthy R et al (2010) DDR1 regulates the stabilization of cell surface E-cadherin and E-cadherin-mediated cell aggregation. J Cell Physiol 224(2):387–397
Hidalgo-Carcedo C et al (2011) Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat Cell Biol 13(1):49–58
Ameli F, Rose IM, Masir N (2015) Expression of DDR1 and DVL1 in invasive ductal and lobular breast carcinoma does not correlate with histological type, grade and hormone receptor status. Asian Pac J Cancer Prev 16(6):2385–2390
Ren T et al (2014) Discoidin domain receptor 2 (DDR2) promotes breast cancer cell metastasis and the mechanism implicates epithelial-mesenchymal transition programme under hypoxia. J Pathol 234(4):526–537
Koh M et al (2015) Discoidin domain receptor 1 is a novel transcriptional target of ZEB1 in breast epithelial cells undergoing H-Ras-induced epithelial to mesenchymal transition. Int J Cancer 136(6):E508–E520
Morikawa A et al (2015) Expression of beclin-1 in the microenvironment of invasive ductal carcinoma of the breast: correlation with prognosis and the cancer-stromal interaction. PLoS One 10(5):e0125762
Lehmann BD et al (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767
Al-Ejeh F et al (2014) Kinome profiling reveals breast cancer heterogeneity and identifies targeted therapeutic opportunities for triple negative breast cancer. Oncotarget 5(10):3145–3158
Mayer IA et al (2014) New strategies for triple-negative breast cancer—deciphering the heterogeneity. Clin Cancer Res 20(4):782–790
Duncan JS et al (2012) Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 149(2):307–321
Cerami E et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404
Gentles AJ et al (2015) The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med 21(8):938–945
Gyorffy B et al (2013) Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One 8(12):e82241
Jezequel P et al (2013) bc-GenExMiner 3.0: new mining module computes breast cancer gene expression correlation analyses. Database (Oxford) 2013:bas060
Taube JH et al (2010) Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A 107(35):15449–15454
Reva B, Antipin Y, Sander C (2011) Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 39(17):e118
Castro-Sanchez L et al (2011) Role of DDR1 in the gelatinases secretion induced by native type IV collagen in MDA-MB-231 breast cancer cells. Clin Exp Metastasis 28(5):463–477
Juin A et al (2014) Discoidin domain receptor 1 controls linear invadosome formation via a Cdc42-Tuba pathway. J Cell Biol 207(4):517–533
Hansen C et al (2006) Phosphorylation of DARPP-32 regulates breast cancer cell migration downstream of the receptor tyrosine kinase DDR1. Exp Cell Res 312(20):4011–4018
Malaguarnera R et al (2015) Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses. Oncotarget 6(18):16084–16105
Yeh YC et al (2011) DDR1 triggers epithelial cell differentiation by promoting cell adhesion through stabilization of E-cadherin. Mol Biol Cell 22(7):940–953
Gao M et al (2013) Discovery and optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors. J Med Chem 56(8):3281–3295
Kim HG et al (2013) Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor. ACS Chem Biol 8(10):2145–2150
L’Hote CG, Thomas PH, Ganesan TS (2002) Functional analysis of discoidin domain receptor 1: effect of adhesion on DDR1 phosphorylation. FASEB J 16(2):234–236
Marcotte R et al (2012) Essential gene profiles in breast, pancreatic, and ovarian cancer cells. Cancer Discov 2(2):172–189
Schlabach MR et al (2008) Cancer proliferation gene discovery through functional genomics. Science 319(5863):620–624
Silva JM et al (2008) Profiling essential genes in human mammary cells by multiplex RNAi screening. Science 319(5863):617–620
Assent D et al (2015) A membrane-type-1 matrix metalloproteinase (MT1-MMP)-discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells. PLoS One 10(3):e0116006
Maquoi E et al (2012) MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis. Oncogene 31(4):480–493
Fu HL et al (2013) Shedding of discoidin domain receptor 1 by membrane-type matrix metalloproteinases. J Biol Chem 288(17):12114–12129
Castro-Sanchez L et al (2010) Native type IV collagen induces cell migration through a CD9 and DDR1-dependent pathway in MDA-MB-231 breast cancer cells. Eur J Cell Biol 89(11):843–852
Neuhaus B et al (2011) Migration inhibition of mammary epithelial cells by Syk is blocked in the presence of DDR1 receptors. Cell Mol Life Sci 68(22):3757–3770
Krisenko MO, Geahlen RL (2015) Calling in SYK: SYK’s dual role as a tumor promoter and tumor suppressor in cancer. Biochim Biophys Acta 1853(1):254–263
Dejmek J et al (2005) Expression and signaling activity of Wnt-5a/discoidin domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival. Clin Cancer Res 11(2 Pt 1):520–528
Paz H, Pathak N, Yang J (2014) Invading one step at a time: the role of invadopodia in tumor metastasis. Oncogene 33(33):4193–4202
Hansen C et al (2009) Wnt-5a-induced phosphorylation of DARPP-32 inhibits breast cancer cell migration in a CREB-dependent manner. J Biol Chem 284(40):27533–27543
Safholm A et al (2006) A formylated hexapeptide ligand mimics the ability of Wnt-5a to impair migration of human breast epithelial cells. J Biol Chem 281(5):2740–2749
Jonsson M, Andersson T (2001) Repression of Wnt-5a impairs DDR1 phosphorylation and modifies adhesion and migration of mammary cells. J Cell Sci 114(Pt 11):2043–2053
Serra R et al (2011) Wnt5a as an effector of TGFbeta in mammary development and cancer. J Mammary Gland Biol Neoplasia 16(2):157–167
Jonsson M et al (2002) Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas. Cancer Res 62(2):409–416
McDonald SL, Silver A (2009) The opposing roles of Wnt-5a in cancer. Br J Cancer 101(2):209–214
Zhu N et al (2014) Challenging role of Wnt5a and its signaling pathway in cancer metastasis (Review). Exp Ther Med 8(1):3–8
Kim ES, Kim MS, Moon A (2004) TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 25(5):1375–1382
Moleirinho S et al (2013) KIBRA exhibits MST-independent functional regulation of the Hippo signaling pathway in mammals. Oncogene 32(14):1821–1830
Barczyk M, Carracedo S, Gullberg D (2010) Integrins. Cell Tissue Res 339(1):269–280
Leitinger B (2011) Transmembrane collagen receptors. Annu Rev Cell Dev Biol 27:265–290
Yu FX, Zhao B, Guan KL (2015) Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163(4):811–828
Dupont S (2015) Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction. Exp Cell Res 343(1):42–53
Dupont S et al (2011) Role of YAP/TAZ in mechanotransduction. Nature 474(7350):179–183
Ghosh S et al (2013) Regulation of adipose oestrogen output by mechanical stress. Nat Commun 4:1821
Corsa CAS et al (2016) The action of Discoidin Domain Receptor 2 in basal tumor cells and stromal cancer-associated fibroblasts is critical for breast cancer metastases. Cell Rep 15(11):2510–2523
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Science+Business Media New York
About this chapter
Cite this chapter
Ekanayaka, S.A., Kleer, C.G., Bollig-Fischer, A., Fernandez-Valdivia, R., Fridman, R. (2016). Discoidin Domain Receptors in Normal Mammary Development and Breast Cancer Progression. In: Fridman, R., Huang, P. (eds) Discoidin Domain Receptors in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-6383-6_7
Download citation
DOI: https://doi.org/10.1007/978-1-4939-6383-6_7
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4939-6381-2
Online ISBN: 978-1-4939-6383-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)