54567

DLL4

delta-like 4 (Drosophila);DLL4;delta-like 4 (Drosophila)

delta 4|delta ligand 4|delta-like 4 homolog|delta-like 4 protein|delta-like protein 4|delta4|drosophila Delta homolog 4|notch ligand DLL4|notch ligand delta-2

15q14

protein-coding

Delta-like ligand 4 (DLL4) is a ligand of the notch pathway. In tumor angiogenesis, DLL4 switches to vascular maturation by providing a negative feedback on VEGFR2 activity. We investigated the expression of DLL4 in the plasma and cancer tissues from breast cancer patients. Plasma samples were collected from 18 women with localized breast cancer, six women with benign breast disease and from six patients with widespread metastatic disease. DLL4 was assessed using ELISA and in cancer tissues using immunohistochemistry. Patients with metastatic breast cancer had significantly higher levels (median 6.7 +/- 0.81 ng/ml) compared to patients with localized tumors (median 5.4 +/- 0.70 ng/ml) (p = 0.005) and to patients with benign breast disease (median 4.3 +/- 0.28) (p = 0.0003). High histology grade was significantly linked with higher plasma DLL4 levels (median 5.59 +/- 0.62 vs. 5.12 +/- 0.44 ng/ml; p = 0.01). Surgical removal of high-grade breast cancer resulted in significant reduction in DLL4 plasma levels (p = 0.003). DLL4 was expressed in tumor-associated vessels and in cancer cells. The ratio of DLL4+/CD31+ vascular density (VD) ranged from 23 to 88% (median 49 %). High DLL4 cancer cell expression and high DLL4+ VD were significantly linked with nodal involvement (p = 0.004 and 0.01, respectively). Linear regression analysis showed a significant association of DLL4 plasma levels with the percentage of DLL4+ cancer cells (p = 0.03, r = 0.50) and with DLL4+ VD (p = 0.0007, r = 0.60). It is concluded that DLL4 is overexpressed in breast cancer cells and breast cancer vasculature and is linked with nodal and distant metastasis. DLL4 plasma levels measurement can reliably estimate the total DLL4 breast cancer/vasculature activity.

delta-Like ligand 4 (DLL4), a ligand for the Notch family of receptors, forecasts the prognosis of several human malignancies. However, the expression and role of DLL4 in breast cancer remain largely unknown. In the present study, we first evaluated whether the overexpression of DLL4 could be used as an indicator of axillary lymph node metastasis and postoperative prognosis in breast cancer. The amount of DLL4 protein was assessed in 204 tumor specimens by immunohistochemical staining. Overexpression was detected in 142 (69.6%) and significantly associated with advanced TNM stage (III versus I, P = .031; III versus II, P = .038), axillary lymph node metastasis (P = .001), and postoperative recurrence (P = .007). Moreover, using univariate and multivariate logistic regression analysis, we found that DLL4 overexpression was strongly associated with axillary lymph node metastasis (odds ratio, 3.036; 95% confidence interval [CI], 1.561, 5.902; P = .001). Lastly, survival analysis showed that patients with low DLL4 expression had a significantly better overall survival and disease-free survival than patients with high DLL4 expression. Furthermore, in multivariate analysis, DLL4 overexpression was an independent risk factor for unfavorable overall survival (hazard ratio, 2.662; 95% CI, 1.300, 5.452; P = .007) and disease-free survival (hazard ratio, 2.568; 95% CI, 1.353, 4.876; P = .004). Taken together, these results suggest that high expression of DLL4 is associated with axillary lymph node metastasis and a poor prognosis in breast cancer, suggesting its value as a diagnostic marker for breast cancer.