Abstract
Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-β, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.
Highlights
Breast and ovarian cancer are amongst the most common female malignancies, with a history of breast cancer linked to a higher risk of ovarian cancer (Mahumud et al, 2019)
DDR1 is activated by binding of wide-ranging types of collagen, whereas DDR2 is exclusively activated by the fibrillar collagens (Leitinger and Kwan, 2006)
Binding of stromal type I collagen to DDR1 on tumor cells, triggers a signaling pathway culminating in the transcriptional up-regulation of pro-apoptotic Bcl-2-interacting killer (BIK), promoting cell growth suppression and central mediator of chondrocyte markers type I collagen (COL1)induced apoptosis (Maquoi et al, 2012; Saby et al, 2019)
Summary
Breast and ovarian cancer are amongst the most common female malignancies, with a history of breast cancer linked to a higher risk of ovarian cancer (Mahumud et al, 2019). The discovery, and understanding the mechanism of action, of novel target molecules dysregulated in female malignancies is central to the development of truly personalized cancer treatments needed to improve patient survival (Bax et al, 2016; Sapiezynski et al, 2016; Emens, 2018; Maennling et al, 2019). Many novel therapeutics target extracellular molecules dysregulated in tumors (e.g., the Her receptor in breast cancer). This approach has the advantage of improved target access for drugs, with the therapeutics not requiring cell entry (Insua-Rodríguez and Oskarsson, 2016; Nakhjavani et al, 2019). Many RTKs have been shown to play critical roles in tumorigenesis, development, and metastasis (Figure 2; Yamaoka et al, 2018; Ghosh et al, 2020)
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