Discoidin domain receptor 1: New star in cancer-targeted therapy and its complex role in breast carcinoma (Review)

  • Authors:
    • Hui Jing
    • Jingyuan Song
    • Junnian Zheng
  • View Affiliations

  • Published online on: January 15, 2018     https://doi.org/10.3892/ol.2018.7795
  • Pages: 3403-3408
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by various types of collagens that performs a critical role in cell attachment, migration, survival and proliferation. The functions of DDR1 in various types of tumor have been studied extensively. However, in breast carcinoma, the roles of collagen‑evoked DDR1 remain ill defined. Although a number of studies have reported that DDR1 promotes apoptosis and inhibits migration in breast carcinoma, it has also been reported to be associated with tumor cell survival, chemoresistance to genotoxic drugs and the facilitation of invasion. The present review summarizes current progress and the complex effects of DDR1 in the field of breast carcinoma, and presents DDR1 as a promising therapeutic target.

Introduction

Discoidin domain receptors (DDRs) are receptor tyrosine kinases (RTKs) characterized by an ~155 amino acid extracellular discoidin homology domain that binds to and is activated by collagens in their native triple-helical form. There are two types of DDR kinases: DDR1 and DDR2. DDR1 is activated by collagens type I–VI and VIII, whereas DDR2 is activated by fibrillar collagens type I and III (13). Alternative splicing generates five DDR1 isoforms: DDR1a, DDR1b, DDR1c, DDR1d and DDR1e. DDR1a, DDR1b and DDR1c are full-length functional receptors, whereas DDR1d and DDR1e are truncated and kinase-inactive receptors (4). DDR1 signaling is required for differentiation, immune response, normal skeletal development, mammary gland branching morphogenesis, migration and wound healing (5). The expression of DDR1 in several different types of human cancer, including breast cancer, renal clear cell carcinoma, non-small cell lung carcinoma, esophageal cancer, astrocytoma, prostate cancer, hepatocellular carcinoma and Hodgkin's lymphoma, suggests a function in tumor progression (614).

Breast carcinoma is the most common type of malignancy in women, with 1.7 million new cases diagnosed worldwide in 2012 (15). Collagens are a major component of the extracellular matrix (ECM); increasing evidence has demonstrated that collagen performs a critical role in the development and progression of breast carcinoma (13,14). In normal breast tissues, if fibrillar collagen deposition is increased, high mammographic density will be detected; it leads to a 2-fold increased risk of breast carcinoma development (16,17). Therefore, DDR1 may serve an important role in breast carcinoma. In renal clear cell carcinoma and a number of other types of cancer, DDR1 was significantly overexpressed in high-grade and advanced-stage tumors (6,12), suggesting that it may be suitable for use as a prognostic marker or therapeutic target. However, in breast carcinoma, the expression of DDR1 and the stage of the cancer do not appear to be associated (18). Different expression levels of DDR1 may be a reflection of its complex effects in breast carcinoma. This review summarizes the current knowledge regarding DDR1 and discusses its complex effects in breast carcinoma.

Collagen-induced DDR1 activation

DDRs are unique among RTKs as they are activated by collagen, an ECM protein. Collagens are major components of the ECM, accounting for ~30% of the total protein mass in the human body (19). Evidence has demonstrated that high mammographic density, which is partly due to increased fibrillar collagen deposition, is associated with a 2-fold increased risk of breast cancer development (16,17). The native triple-helical collagen serves as a ligand of DDR1; DDR1 cannot be activated by heat-denatured collagen (20,21). DDR1 is activated by specific types of collagens, as aforementioned. The DDR collagen-binding sites are entirely contained within the discoidin 1 domains (13). Leitinger et al (21) demonstrated that the isolated discoidin 1 domains of DDR1 and DDR2 bind directly to collagen with high affinity and that binding requires these domains to be dimerized. Initial mutagenesis experiments mapped the collagen-binding sites to three spatially adjacent surface-exposed loops that are highly conserved between the DDRs (21,22). DDR1 and DDR2 bind the GVMGVO (O, hydroxyproline) motif within fibrillar collagens I–III (2325). Analysis revealed that the activation of DDR1 by collagen results in the binding of CD9 to Tyr513, SH2-domain containing protein to Tyr703, 796 and 740, and the p85 subunit of phosphoinositide 3-kinase to Tyr881 (20,2628). These interactions were confirmed and additional binding proteins, including Ras GTPase activating protein, SH-2 domain-containing inositol 5′ polyphosphatase (SHIP)1, SHIP2, signal transducer and activator of transcription and SRC family kinases, were identified using proteomics approaches (29). Therefore, following binding to collagen, DDR1 becomes phosphorylated at tyrosine residues and can activate various downstream signaling pathways.

DDR1 expression level in breast carcinoma

Studies with large sets of clinical follow-up data and patients have been performed to verify the DDR1 expression profiles of different histological types of breast carcinoma (Table I). Invasive ductal and lobular carcinomas are the most common histological types of breast carcinoma (30,31). DDR1 was identified to be differentially expressed between lobular and ductal carcinomas by a pairwise comparison analysis (32). DDR1 was overexpressed in ductal carcinomas, as confirmed by immunohistochemistry, in which DDR1 was positive in 96.2% of ductal carcinomas compared with only 13.8% of lobular carcinomas (33). Considering this, DDR1 may represent a novel tissue marker in the differentiation of ductal and lobular breast carcinoma as an addition to the well-established marker E-cadherin (3234). In triple-negative breast carcinoma, a DDR1low/DDR2high subtype has been identified that may be more invasive and associated with a worse prognosis (13). In human breast cancer stem cells with the CD44highCD24low phenotype, DDR1 expression was reduced (3537). In other histological types of breast carcinoma, the expression level of DDR1 is lower in the more mesenchymal and invasive Basal B type cell lines, a subtype with enhanced invasive properties (38). Overall, the DDR1 expression profiles of different histological types of breast carcinoma may vary, as summarized in Table I.

Table I.

Expression levels of DDR1 in different types of breast carcinoma.

Table I.

Expression levels of DDR1 in different types of breast carcinoma.

DDR1 expression

Breast cancer typeHighLow
Metastasis-containing lymph nodes(83)
Ductal carcinoma in situ(13,84)
Invasive ductal carcinoma(32,48,85)
Invasive lobular carcinoma (32,84,85)
Middle to high-grade carcinoma (54)
Triple-negative breast carcinoma (13,84)

[i] DDR1, discoidin domain receptor 1.

DDR1 association with EMT in breast carcinoma

The epithelial-to-mesenchymal transition (EMT) program promotes cell motility, invasion and metastasis (3941). EMT is characterized by an increase in cell motility, invasiveness and stem cell-like properties. Tumor cells that undergo EMT express fewer epithelial markers, including E-cadherin and cytokeratins, but express more mesenchymal markers, including vimentin and N-cadherin, with a possible switch in DDR expression from DDR1 (epithelial) to DDR2 (mesenchymal) (42,43). DDR1, as opposed to DDR2, is downregulated to induce the expression of the EMT transcription factors Twist and Snail in breast epithelial cells, suggesting a differential regulation of DDRs during the development of EMT (2,44,45). In breast carcinoma cells, DDR1 negatively regulates EMT. DDR1 is expressed predominantly in regions of cell-cell contact, where it interacts with and stabilizes E-cadherin in normal epithelial cells (4649). Studies on tissue samples of patients with breast cancer also demonstrate a negative correlation between DDR1 and zinc finger E-box-binding homeobox 1 (ZEB1) expression. ZEB1 is a key regulator of the EMT program in human breast cancer cells and can directly suppress the transcription of E-cadherin to promote EMT (33). Therefore, when the expression level of DDR1 is high, it may inhibit ZEB1 and the EMT program. Furthermore, the overexpression of DDR1a or DDR1b reduces the invasive phenotype and regulates the F-actin cytoskeletal organization of breast cancer cells (46). Therefore, in breast cancer cells, DDR1 serves a negative function in the EMT program.

Complex role of DDR1 in migration

Studies have demonstrated that DDR1 functions in the regulation of cell adhesion and migration in tumors (5053). Neuhaus et al (54) used chemokine-driven transwell migration assays to assess the migration of small interfering RNA (siRNA)-transfected cells and detected a marked reduction of cell migration following the knockdown of DDR1 in T47D and MDA-MB-468 breast cancer cell lines; T47D cell migration was reduced by 23% and MDA-MB-468 migration by 57%. It was concluded that when DDR1 is downregulated, the migration ability is also decreased. A study has demonstrated that DDR1 can mediate cell migration by means of regulating the migration suppressor Syk kinase (55), providing further evidence for a pro-migratory role of DDR1. Castro-Sanchez et al (56) demonstrated that in MDA-MB-231 breast cancer cells, DDR1 mediates matrix metalloproteinase (MMP)-2 and-9 secretion and invasion induced by native type IV collagen. In NIH3T3 fibroblasts and MCF7 breast cancer cells, DDR1 was demonstrated to inhibit cell spreading, but to promote migration, via interaction with non-muscle myosin heavy chain-IIA, a contractile protein associated with cell spreading (57). Furthermore, native type IV collagen induces a transient increase of CD9-cell surface levels and cell migration through a DDR1 and CD9-dependent pathway in MDA-MB-231 breast cancer cells (58). Therefore, numerous studies demonstrate that DDR1 performs a pro-migratory function (Fig. 1).

However, Hansen et al (59) reported an opposite effect of DDR1; they identified that in the MCF-7 and MDA-MB-231 breast cancer cell lines, DDR1 suppressed migration when co-expressed with its interacting partner, dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32). In the presence of DDR1, DARPP-32 was confined to a restricted subcellular location at the plasma membrane, which induced an anti-migratory function in various breast cancer cell lines (59). However, this anti-migration function did not require DDR1 activation, in contrast with the study by Neuhaus et al (54). Furthermore, Jonsson et al (52) reported that a reduced extent of DDR1 tyrosine phosphorylation in Wnt-5a antisense cells promoted cell scattering, enhanced cell motility and impaired cell-collagen interaction. Wnt-5a may activate DDR1 to inhibit migration in non-malignant human mammary epithelial cells (52). Wnt gene families encode signaling glycoproteins that are associated with embryogenesis and the regulation of normal and pathological cell processes (6062). Wnts are implicated in tumor formation; the endogenous expression of Wnt-5a is sufficient to enable the collagen-induced phosphorylation of DDR1 receptors in MCF-7 (6365). Roarty and Serra (66) demonstrated that the negative interference of transforming growth factor-β signaling not only affected the expression of Wnt-5a, but also the phosphorylation of DDR1, a downstream target of Wnt-5a associated with cell migration. Overall, the effect of DDR1 on migration may depend on interacting factors.

DDR1 in breast carcinoma invasion

Regarding the role of DDR1 in invasion, accumulating evidence produced with matrigel invasion assays indicates that DDR1 can promote invasion in a number of types of human cancer cell line, including breast (56), lung (8), prostate (9), pituitary adenoma (67), hepatocellular carcinoma (14) and glioma (68,69). The pro-invasive function of DDR1 may be mediated by the upregulation of the expression of MMPs, particularly MMP-2 and MMP-9. The elevated expression of MMPs contributes to the degradation of extracellular matrix components, facilitating cancer cell invasion (56). Products that can suppress the pro-invasion function of DDR1 have been developed; Santa Cruz Biotechnology have developed two novel antibodies that can inhibit DDR1a-mediated Matrigel invasion (68) and DDR1 activation in human MDA-MB-231 cells (58). Therefore, previous studies predominantly support that DDR1 promotes invasion in breast cancer.

Effects of DDR1 on the apoptosis or survival of breast cancer cells

Varying DDR1 expression levels have been identified in a variety of types of human cancer. Assent et al (70) identified that in breast cancer, DDR1 performed a role in monitoring the cellular microenvironment and triggering apoptosis via the induction of Bcl-2-interacting killer. To confirm that apoptosis could be induced by DDR1, they used siRNA to reduce the DDR1 expression level in MCF-7 cells and incubated them with collagen gels. They determined that the downregulation of DDR1 inhibited apoptosis by ~60% in breast cancer cells. A further study identified that the catalytic activity of membrane type-1-MMP (MT1-MMP) impaired this DDR1-initiated apoptotic program, although the mechanisms by which MT1-MMP may interfere with DDR1-initiated signaling remain unclear (70).

DDR1 can induce pro- (5,44,69,71,72) and anti- (7375) proliferative effects depending on the cell type. It was previously demonstrated that in KRAS-driven lung adenocarcinoma, DDR1 and Notch co-inhibition suppressed the activation of critical tumor survival-promoting signaling pathways (76). High DDR1 expression may also exhibit a positive effect in the proliferation and/or survival of breast cancer cells (46,77). Ongusaha et al (78) demonstrated that the DDR1 receptor could function as a survival effector in wild-type p53-containing breast cancer cells exposed to genotoxic drugs. Furthermore, Fanale et al (79) reported that the DDR1 pathway is likely to be an alternative to the established pro-growth and survival signaling pathways in tumor cells, as activated DDR1 significantly increased tumor cell survival in vitro. Therefore, we hypothesize that in breast carcinoma, the DDR1 pathway may be pro-apoptotic or pro-survival, depending on the microenvironment.

DDR1 enhances the chemoresistance to genotoxic drugs

Previous studies have demonstrated that DDR1 is a direct transcriptional target of p53. In wild-type p53-containing cells exposed to genotoxic drugs, DDR1 can function as a survival effector (78). During genotoxic stress, the inhibition of DDR1 function led to the markedly increased apoptosis of wild-type p53-containing cells via a caspase-dependent pathway (78). Das (80) reported that DDR1 induced cyclooxygenase-2 (COX-2) expression, resulting in enhanced chemoresistance in MDA-MB-435 and T47D breast cancer cells. Subsequent to using short hairpin RNA against DDR1 to eliminate DDR1-mediated COX-2 induction, they identified that the chemosensitivity of the breast cancer cells was increased. They also demonstrated that DDR1 activated the nuclear factor-κB (NF-κB) pathway under genotoxic stress. When they inhibited the activation of the NF-κB pathway, the level of DDR1-induced COX-2 was reduced, leading to enhanced breast cancer cell chemosensitivity. Therefore, DDR1-mediated COX-2 induction was NF-κB-dependent (80). However, the effect of DDR1 on genotoxic drug resistance requires further study.

Conclusions

The present review described the complex functions of DDR1 in regulating EMT, migration, invasion, apoptosis, survival and chemoresistance to genotoxic drugs in breast carcinoma, as well as illustrating the identified up/downstream signaling molecules that mediate these effects (Table II, Fig. 1). The effects of DDR1 expression in breast carcinoma may depend on the histological type, grade and hormone receptor status of the tumor (Table I). Considering the critical role of collagen-induced DDR1 in the migration, invasion, apoptosis and chemoresistance of breast carcinoma cells, the associated molecular mechanisms require further investigation.

Table II.

In vitro functions of discoidin domain receptor 1 in breast carcinoma progression.

Table II.

In vitro functions of discoidin domain receptor 1 in breast carcinoma progression.

ProcessPositive regulatorNegative regulator
Proliferation/survivalMCF-7 (78)MCF-7 and ZR-75-1 (70,86)
MDA-MB-435 and T47D (80)
MigrationMCF-7 (57)MCF-7 (59)
MDA-MB-231 (58)MDA-MB-231 (46,59)
MDA-MB-468 and T47D (54)Hs578T (46)
InvasionMDA-MB-231 (58,87)Not reported
Epithelial-to-mesenchymal transitionNot reportedHs578T, MCF-7 and MDA-MB-231 (46)

In summary, regulation via DDR1 may be critical for breast tumor suppression or promotion and therefore, the development of small-molecule drugs targeting DDR1 may be a novel strategy for anticancer therapy according to the histological type, grade and hormone receptor status of the breast tumor. To the present day, studies have identified imatinib, nilotinib and dasatinib as DDR1 inhibitors (81,82).

Acknowledgements

The present study was supported by the National Natural Science Foundation of China (grant no. 81301806), Jiangsu Planned Projects for Postdoctoral Research Funds (grant no. 1501060A), Jiangsu Overseas Research & Training Program for University Prominent Young & Middle-aged Teachers and Presidents and the Jiangsu Province Graduate Innovation Project (grant no. SJLX15_0727).

References

1 

Vogel WF, Abdulhussein R and Ford CE: Sensing extracellular matrix: An update on discoidin domain receptor function. Cell Signal. 18:1108–1116. 2006. View Article : Google Scholar : PubMed/NCBI

2 

Valiathan RR, Marco M, Leitinger B, Kleer CG and Fridman R: Discoidin domain receptor tyrosine kinases: New players in cancer progression. Cancer Metastasis Rev. 31:295–321. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, Davis S, Goldfarb MP, Glass DJ, Lemke G and Yancopoulos GD: An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol Cell. 1:25–34. 1997. View Article : Google Scholar : PubMed/NCBI

4 

Playford MP, Butler RJ, Wang XC, Katso RM, Cooke IE and Ganesan TS: The genomic structure of discoidin receptor tyrosine kinase. Genome Res. 6:620–627. 1996. View Article : Google Scholar : PubMed/NCBI

5 

Hou G, Vogel W and Bendeck MP: The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair. J Clin Invest. 107:727–735. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Quan J, Yahata T, Adachi S, Yoshihara K and Tanaka K: Identification of receptor tyrosine kinase, discoidin domain receptor 1 (DDR1), as a potential biomarker for serous ovarian cancer. Int J Mol Sci. 12:971–982. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Nakada M, Kita D, Teng L, Pyko IV, Watanabe T, Hayashi Y and Hamada J: Receptor tyrosine kinases: Principles and functions in glioma invasion. Adv Exp Med Biol. 986:143–170. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Yang SH, Baek HA, Lee HJ, Park HS, Jang KY, Kang MJ, Lee DG, Lee YC, Moon WS and Chung MJ: Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung carcinomas. Oncol Rep. 24:311–319. 2010.PubMed/NCBI

9 

Shimada K, Nakamura M, Ishida E, Higuchi T, Yamamoto H, Tsujikawa K and Konishi N: Prostate cancer antigen-1 contributes to cell survival and invasion though discoidin receptor 1 in human prostate cancer. Cancer Sci. 99:39–45. 2008.PubMed/NCBI

10 

Nemoto T, Ohashi K, Akashi T, Johnson JD and Hirokawa K: Overexpression of protein tyrosine kinases in human esophageal cancer. Pathobiology. 65:195–203. 1997. View Article : Google Scholar : PubMed/NCBI

11 

Willenbrock K, Kuppers R, Renne C, Brune V, Eckerle S, Weidmann E, Bräuninger A and Hansmann ML: Common features and differences in the transcriptome of large cell anaplastic lymphoma and classical Hodgkin's lymphoma. Haematologica. 91:596–604. 2006.PubMed/NCBI

12 

Song J, Chen X, Bai J, Liu Q, Li H, Xie J, Jing H and Zheng J: Discoidin domain receptor 1 (DDR1), a promising biomarker, induces epithelial to mesenchymal transition in renal cancer cells. Tumour Biol. 37:11509–11521. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Toy KA, Valiathan RR, Núñez F, Kidwell KM, Gonzalez ME, Fridman R and Kleer CG: Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer. Breast Cancer Res Treat. 150:9–18. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Shen Q, Cicinnati VR, Zhang X, Iacob S, Weber F, Sotiropoulos GC, Radtke A, Lu M, Paul A, Gerken G and Beckebaum S: Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion. Mol Cancer. 9:2272010. View Article : Google Scholar : PubMed/NCBI

15 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Maskarinec G, Pagano IS, Little MA, Conroy SM, Park SY and Kolonel LN: Mammographic density as a predictor of breast cancer survival: The Multiethnic Cohort. Breast Cancer Res. 15:R72013. View Article : Google Scholar : PubMed/NCBI

17 

Tice JA, O'Meara ES, Weaver DL, Vachon C, Ballard-Barbash R and Kerlikowske K: Benign breast disease, mammographic breast density and the risk of breast cancer. J Natl Cancer Inst. 105:1043–1049. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Ameli F, Rose IM and Masir N: 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. 16:2385–2390. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Egeblad M, Rasch MG and Weaver VM: Dynamic interplay between the collagen scaffold and tumor evolution. Current Opin Cell Biol. 22:697–706. 2010. View Article : Google Scholar

20 

Vogel W, Gish GD, Alves F and Pawson T: The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1:13–23. 1997. View Article : Google Scholar : PubMed/NCBI

21 

Leitinger B: Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2. Identification of collagen binding sites in DDR2. J Biol Chem. 278:16761–16769. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Abdulhussein R, McFadden C, Fuentes-Prior P and Vogel WF: Exploring the collagen-binding site of the DDR1 tyrosine kinase receptor. J Biol Chem. 279:31462–31470. 2004. View Article : Google Scholar : PubMed/NCBI

23 

Konitsiotis AD, Raynal N, Bihan D, Hohenester E, Farndale RW and Leitinger B: Characterization of high affinity binding motifs for the discoidin domain receptor DDR2 in collagen. J Biol Chem. 283:6861–6868. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Xu H, Raynal N, Stathopoulos S, Myllyharju J, Farndale RW and Leitinger B: Collagen binding specificity of the discoidin domain receptors: Binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1. Matrix Biol. 30:16–26. 2011. View Article : Google Scholar : PubMed/NCBI

25 

Leitinger B: Transmembrane collagen receptors. Annu Rev Cell Dev Biol. 27:265–290. 2011. View Article : Google Scholar : PubMed/NCBI

26 

L'Hote CG, Thomas PH and Ganesan TS: Functional analysis of discoidin domain receptor 1: Effect of adhesion on DDR1 phosphorylation. FASEB J. 16:234–236. 2002. View Article : Google Scholar : PubMed/NCBI

27 

Koo DH, McFadden C, Huang Y, Abdulhussein R, Friese-Hamim M and Vogel WF: Pinpointing phosphotyrosine-dependent interactions downstream of the collagen receptor DDR1. FEBS Lett. 580:15–22. 2006. View Article : Google Scholar : PubMed/NCBI

28 

Wang CZ, Su HW, Hsu YC, Shen MR and Tang MJ: A discoidin domain receptor 1/SHP-2 signaling complex inhibits alpha2beta1-integrin-mediated signal transducers and activators of transcription 1/3 activation and cell migration. Mol Biol Cell. 17:2839–2852. 2006. View Article : Google Scholar : PubMed/NCBI

29 

Lemeer S, Bluwstein A, Wu Z, Leberfinger J, Müller K, Kramer K and Kuster B: Phosphotyrosine mediated protein interactions of the discoidin domain receptor 1. J Proteomics. 75:3465–3477. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Nascimento AF, Raut CP and Fletcher CD: Primary angiosarcoma of the breast: Clinicopathologic analysis of 49 cases, suggesting that grade is not prognostic. Am J Surg Pathol. 32:1896–1904. 2008. View Article : Google Scholar : PubMed/NCBI

31 

Petridis C, Brook MN, Shah V, Kohut K, Gorman P, Caneppele M, Levi D, Papouli E, Orr N, Cox A, et al: Genetic predisposition to ductal carcinoma in situ of the breast. Breast Cancer Res. 18:222016. View Article : Google Scholar : PubMed/NCBI

32 

Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J, et al: Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer. 7:552007. View Article : Google Scholar : PubMed/NCBI

33 

Spaderna S, Schmalhofer O, Wahlbuhl M, Dimmler A, Bauer K, Sultan A, Hlubek F, Jung A, Strand D, Eger A, et al: The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res. 68:537–544. 2008. View Article : Google Scholar : PubMed/NCBI

34 

Dejmek J, Dib K, Jonsson M and Andersson T: Wnt-5a and G-protein signaling are required for collagen-induced DDR1 receptor activation and normal mammary cell adhesion. Int J Cancer. 103:344–351. 2003. View Article : Google Scholar : PubMed/NCBI

35 

Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 100:3983–3988. 2003. View Article : Google Scholar : PubMed/NCBI

36 

Islam N, Kwon SC, Senie R and Kathuria N: Breast and cervical cancer screening among South Asian women in New York city. J Immigr Minor Health. 8:211–221. 2006. View Article : Google Scholar : PubMed/NCBI

37 

Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, et al: Molecular definition of breast tumor heterogeneity. Cancer Cell. 11:259–273. 2007. View Article : Google Scholar : PubMed/NCBI

38 

Blick T, Hugo H, Widodo E, Waltham M, Pinto C, Mani SA, Weinberg RA, Neve RM, Lenburg ME and Thompson EW: Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44 (hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. J Mammary Gland Biol Neoplasia. 15:235–252. 2010. View Article : Google Scholar : PubMed/NCBI

39 

Sheen YY, Kim MJ, Park SA, Park SY and Nam JS: Targeting the transforming growth factor-β signaling in cancer therapy. Biomol Ther (Seoul). 21:323–331. 2013. View Article : Google Scholar : PubMed/NCBI

40 

Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI

41 

Savagner P: Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays. 23:912–923. 2001. View Article : Google Scholar : PubMed/NCBI

42 

Hay ED: An overview of epithelio-mesenchymal transformation. Acta Anat (Basel). 154:8–20. 1995. View Article : Google Scholar : PubMed/NCBI

43 

Savagner P, Boyer B, Valles AM, Jouanneau J and Thiery JP: Modulations of the epithelial phenotype during embryogenesis and cancer progression. Cancer Treat Res. 71:229–249. 1994. View Article : Google Scholar : PubMed/NCBI

44 

Maeyama M, Koga H, Selvendiran K, Yanagimoto C, Hanada S, Taniguchi E, Kawaguchi T, Harada M, Ueno T and Sata M: Switching in discoid domain receptor expressions in SLUG-induced epithelial-mesenchymal transition. Cancer. 113:2823–2831. 2008. View Article : Google Scholar : PubMed/NCBI

45 

Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, Hartwell K, Onder TT, Gupta PB, Evans KW, et al: Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA. 107:15449–15454. 2010. View Article : Google Scholar : PubMed/NCBI

46 

Koh M, Woo Y, Valiathan RR, Jung HY, Park SY, Kim YN, Kim HR, Fridman R and Moon A: 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:E508–E520. 2015. View Article : Google Scholar : PubMed/NCBI

47 

Yeh YC, Wu CC, Wang YK and Tang MJ: DDR1 triggers epithelial cell differentiation by promoting cell adhesion through stabilization of E-cadherin. Mol Biol Cell. 22:940–953. 2011. View Article : Google Scholar : PubMed/NCBI

48 

Hidalgo-Carcedo C, Hooper S, Chaudhry SI, Williamson P, Harrington K, Leitinger B and Sahai E: 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. 13:49–58. 2011. View Article : Google Scholar : PubMed/NCBI

49 

Eswaramoorthy R, Wang CK, Chen WC, Tang MJ, Ho ML, Hwang CC, Wang HM and Wang CZ: DDR1 regulates the stabilization of cell surface E-cadherin and E-cadherin-mediated cell aggregation. J Cell Physiol. 224:387–397. 2010. View Article : Google Scholar : PubMed/NCBI

50 

Wang L, Devarajan E, He J, Reddy SP and Dai JL: Transcription repressor activity of spleen tyrosine kinase mediates breast tumor suppression. Cancer Res. 65:10289–10297. 2005. View Article : Google Scholar : PubMed/NCBI

51 

Kamohara H, Yamashiro S, Galligan C and Yoshimura T: Discoidin domain receptor 1 isoform-a (DDR1alpha) promotes migration of leukocytes in three-dimensional collagen lattices. FASEB J. 15:2724–2726. 2001. View Article : Google Scholar : PubMed/NCBI

52 

Jonsson M and Andersson T: Repression of Wnt-5a impairs DDR1 phosphorylation and modifies adhesion and migration of mammary cells. J Sci. 114:2043–2053. 2001.

53 

Hou G, Vogel WF and Bendeck MP: Tyrosine kinase activity of discoidin domain receptor 1 is necessary for smooth muscle cell migration and matrix metalloproteinase expression. Circ Res. 90:1147–1149. 2002. View Article : Google Scholar : PubMed/NCBI

54 

Neuhaus B, Bühren S, Böck B, Alves F, Vogel WF and Kiefer F: Migration inhibition of mammary epithelial cells by Syk is blocked in the presence of DDR1 receptors. Cell Mol Life Sci. 68:3757–3770. 2011. View Article : Google Scholar : PubMed/NCBI

55 

Dejmek J, Leandersson K, Manjer J, Bjartell A, Emdin SO, Vogel WF, Landberg G and Andersson T: 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. 11:520–528. 2005.PubMed/NCBI

56 

Castro-Sanchez L, Soto-Guzman A, Guaderrama-Diaz M, Cortes-Reynosa P and Salazar EP: Role of DDR1 in the gelatinases secretion induced by native type IV collagen in MDA-MB-231 breast cancer cells. Clin Exp Metastasis. 28:463–477. 2011. View Article : Google Scholar : PubMed/NCBI

57 

Huang Y, Arora P, McCulloch CA and Vogel WF: The collagen receptor DDR1 regulates cell spreading and motility by associating with myosin IIA. J Cell Sci. 122:1637–1646. 2009. View Article : Google Scholar : PubMed/NCBI

58 

Castro-Sanchez L, Soto-Guzman A, Navarro-Tito N, Martinez-Orozco R and Salazar EP: 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. 89:843–852. 2010. View Article : Google Scholar : PubMed/NCBI

59 

Hansen C, Greengard P, Nairn AC, Andersson T and Vogel WF: Phosphorylation of DARPP-32 regulates breast cancer cell migration downstream of the receptor tyrosine kinase DDR1. Exp Cell Res. 312:4011–4018. 2006. View Article : Google Scholar : PubMed/NCBI

60 

Dierick H and Bejsovec A: Cellular mechanisms of wingless/Wnt signal transduction. Curr Top Dev Biol. 43:153–190. 1999. View Article : Google Scholar : PubMed/NCBI

61 

Pruitt MM, Letcher EJ, Chou HC, Bastin BR and Schneider SQ: Expression of the wnt gene complement in a spiral-cleaving embryo and trochophore larva. Int J Dev Biol. 58:563–573. 2014. View Article : Google Scholar : PubMed/NCBI

62 

Dale TC: Signal transduction by the Wnt family of ligands. Biochem J. 329:209–223. 1998. View Article : Google Scholar : PubMed/NCBI

63 

Brennan KR and Brown AM: Wnt proteins in mammary development and cancer. J Mammary Gland Biol Neoplasia. 9:119–131. 2004. View Article : Google Scholar : PubMed/NCBI

64 

Katoh M: WNT/PCP signaling pathway and human cancer (Review). Oncol Rep. 14:1583–1588. 2005.PubMed/NCBI

65 

Yang Y: Wnt signaling in development and disease. Cell Biosci. 2:142012. View Article : Google Scholar : PubMed/NCBI

66 

Roarty K and Serra R: Wnt5a is required for proper mammary gland development and TGF-beta-mediated inhibition of ductal growth. Development. 134:3929–3939. 2007. View Article : Google Scholar : PubMed/NCBI

67 

Yoshida D and Teramoto A: Enhancement of pituitary adenoma cell invasion and adhesion is mediated by discoidin domain receptor-1. J Neurooncol. 82:29–40. 2007. View Article : Google Scholar : PubMed/NCBI

68 

Ram R, Lorente G, Nikolich K, Urfer R, Foehr E and Nagavarapu U: Discoidin domain receptor-1a (DDR1a) promotes glioma cell invasion and adhesion in association with matrix metalloproteinase-2. J Neurooncol. 76:239–248. 2006. View Article : Google Scholar : PubMed/NCBI

69 

Yamanaka R, Arao T, Yajima N, Tsuchiya N, Homma J, Tanaka R, Sano M, Oide A, Sekijima M and Nishio K: Identification of expressed genes characterizing long-term survival in malignant glioma patients. Oncogene. 25:5994–6002. 2006. View Article : Google Scholar : PubMed/NCBI

70 

Assent D, Bourgot I, Hennuy B, Geurts P, Noël A, Foidart JM and Maquoi E: A Membrane-Type-1 Matrix Metalloproteinase (MT1-MMP)-discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells. PLoS One. 10:e01160062015. View Article : Google Scholar : PubMed/NCBI

71 

Roberts ME, Magowan L, Hall IP and Johnson SR: Discoidin domain receptor 1 regulates bronchial epithelial repair and matrix metalloproteinase production. Eur Respir J. 37:1482–1493. 2011. View Article : Google Scholar : PubMed/NCBI

72 

Dang N, Hu J, Liu X, Li X, Ji S, Zhang W, Su J, Lu F, Yang A, Han H, et al: CD167 acts as a novel costimulatory receptor in T-cell activation. J Immunother. 32:773–784. 2009. View Article : Google Scholar : PubMed/NCBI

73 

Vogel WF, Aszódi A, Alves F and Pawson T: Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development. Mol Cell Biol. 21:2906–2917. 2001. View Article : Google Scholar : PubMed/NCBI

74 

Curat CA and Vogel WF: Discoidin domain receptor 1 controls growth and adhesion of mesangial cells. J Am Soc Nephrol. 13:2648–2656. 2002. View Article : Google Scholar : PubMed/NCBI

75 

Franco C, Ahmad PJ, Hou G, Wong E and Bendeck MP: Increased cell and matrix accumulation during atherogenesis in mice with vessel wall-specific deletion of discoidin domain receptor 1. Circ Res. 106:1775–1783. 2010. View Article : Google Scholar : PubMed/NCBI

76 

Ambrogio C, Gomez-Lopez G, Falcone M, Vidal A, Nadal E, Crosetto N, Blasco RB, Fernández-Marcos PJ, Sánchez-Céspedes M, Ren X, et al: Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nat Med. 22:270–277. 2016. View Article : Google Scholar : PubMed/NCBI

77 

Duncan JS, Whittle MC, Nakamura K, Abell AN, Midland AA, Zawistowski JS, Johnson NL, Granger DA, Jordan NV, Darr DB, et al: Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell. 149:307–321. 2012. View Article : Google Scholar : PubMed/NCBI

78 

Ongusaha PP, Kim JI, Fang L, Wong TW, Yancopoulos GD, Aaronson SA and Lee SW: p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop. EMBO J. 22:1289–1301. 2003. View Article : Google Scholar : PubMed/NCBI

79 

Fanale M: Activated DDR1 increases RS cell survival. Blood. 122:4152–4154. 2013. View Article : Google Scholar : PubMed/NCBI

80 

Das S: Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-B pathway activation. Cancer Res. 66:8123–8130. 2006. View Article : Google Scholar : PubMed/NCBI

81 

Rix U, Hantschel O, Duernberger G, Rix Remsing LL, Planyavsky M, Fernbach NV, Kaupe I, Bennett KL, Valent P, Colinge J, et al: Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib, reveal novel kinase and nonkinase targets. Blood. 110:4055–4063. 2007. View Article : Google Scholar : PubMed/NCBI

82 

Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, Mathieson T, Perrin J, Raida M, Rau C, et al: Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 25:1035–1044. 2007. View Article : Google Scholar : PubMed/NCBI

83 

Barker KT, Martindale JE, Mitchell PJ, Kamalati T, Page MJ, Phippard DJ, Dale TC, Gusterson BA and Crompton MR: Expression patterns of the novel receptor-like tyrosine kinase, Ddr, in human breast-tumors. Oncogene. 10:569–575. 1995.PubMed/NCBI

84 

Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature. 490:61–70. 2012. View Article : Google Scholar : PubMed/NCBI

85 

Turashvilia G, Bouchala J, Ehrmanna J, Kolara Z, Fridmanb E and Skardaa J: Novel immunohistochemical markers for the differentiation of lobular and ductal invasive breast carcinomas. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 151:59–64. 2007. View Article : Google Scholar : PubMed/NCBI

86 

Maquoi E, Assent D, Detilleux J, Pequeux C, Foidart JM and Noël A: MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis. Oncogene. 31:480–493. 2012. View Article : Google Scholar : PubMed/NCBI

87 

Juin A, Di Martino J, Leitinger B, Henriet E, Gary AS, Paysan L, Bomo J, Baffet G, Gauthier-Rouvière C, Rosenbaum J, et al: Discoidin domain receptor 1 controls linear invadosome formation via a Cdc42-Tuba pathway. J Cell Biol. 207:517–533. 2014. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

March-2018
Volume 15 Issue 3

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Jing H, Song J and Zheng J: Discoidin domain receptor 1: New star in cancer-targeted therapy and its complex role in breast carcinoma (Review). Oncol Lett 15: 3403-3408, 2018.
APA
Jing, H., Song, J., & Zheng, J. (2018). Discoidin domain receptor 1: New star in cancer-targeted therapy and its complex role in breast carcinoma (Review). Oncology Letters, 15, 3403-3408. https://doi.org/10.3892/ol.2018.7795
MLA
Jing, H., Song, J., Zheng, J."Discoidin domain receptor 1: New star in cancer-targeted therapy and its complex role in breast carcinoma (Review)". Oncology Letters 15.3 (2018): 3403-3408.
Chicago
Jing, H., Song, J., Zheng, J."Discoidin domain receptor 1: New star in cancer-targeted therapy and its complex role in breast carcinoma (Review)". Oncology Letters 15, no. 3 (2018): 3403-3408. https://doi.org/10.3892/ol.2018.7795