Expression of vascular endothelial growth factor D is associated with hypoxia inducible factor (HIF-1α) and the HIF-1α target gene DEC1, but not lymph node metastasis in primary human breast carcinomas

Abstract

Background:Vascular endothelial growth factor D (VEGF-D) induces angiogenesis and lymphangiogenesis. Nodal metastasis is recognised as a powerful prognostic marker in breast carcinoma, but the molecular mechanisms underlying this process are unknown. Although it has been suggested that VEGF-D may regulate nodal metastasis, this is based largely on animal models, its role in human disease being unclear.Aims:To measure the pattern and degree of VEGF-D protein expression in normal and neoplastic human breast tissues.Methods:The pattern and degree of VEGF-D expression was measured in normal tissue and invasive carcinomas, and expression was correlated with clinicopathological parameters, hypoxia markers, and survival. Because other VEGF family members are affected by oestrogen, whether VEGF-D is regulated by oestrogen in breast cancer cell lines was also assessed.Results:VEGF-D was significantly positively associated with hypoxia inducible factor (HIF-1α) (p = 0.03) and the HIF-1α regulated gene DEC1 (p = 0.001), but not lymph node status, the number of involved lymph nodes, patient age, tumour size, tumour grade, lymphovascular invasion, oestrogen receptor, progesterone receptor, c-erb-B2, or tumour histology (all p>0.05). There was no significant relation between tumour VEGF-D expression and relapse free (p = 0.78) or overall (p = 0.94) survival. VEGF-D expression was enhanced by oestrogen in MCF-7 and T47D breast cancer cells, and was blocked by hydroxytamoxifen.Conclusion:These findings support a role for hypoxia and oestrogen induced VEGF-D in human breast cancer and also suggest that tamoxifen and related oestrogen antagonists may exert some of their antitumour effects through the abrogation of VEGF-D induced function.

Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer

“…We have also critically compared the use of tissue microarrays for the analysis of hypoxia markers in female breast cancer and found equivalent frequencies of expression with other studies that had used whole sections. 31,32 We feel this is a robust and well established methodology, and as our staining frequencies in male breast cancer are similar to Kornegoor et al, 18 our detection rates were not substantially compromised. Although there are low numbers of BRCA1 cases, reflecting the general paucity of these tumors within male breast cancer registries, our findings show that a decreased expression of hypoxia markers is characteristic of male breast cancers.…”

Breast cancer metastasis and the lymphatic system

“…The growth rate of the tumor, angiogenesis and the formation of metastases appear to be promoted by VEGF-D (45). However, other studies conducted to investigate the association of VEGF-C and VEGF-D expression with metastasis have resulted in contradictory conclusions (46,47). These ambiguous results may be attributed to tumor microenvironment variations, including degrees of proteolytic processing, dissimilarities in tumor tissues, and interactions with other lymphangiogenic factors.…”

Expression of Vascular Endothelial Growth Factors VEGF- C and D, VEGFR-3, and Comparison of Lymphatic Vessels Density Labeled with D2-40 Antibodies as a Prognostic Factors in Vulvar Intraepithelial Neoplasia (VIN) and Invasive Vulvar Cancer

“…Overexpression of VEGF-C and-D in experimental tumor models was accompanied by intensive growth of new lymphatic vessels (Skobe et al 2001), but in human tumors, these molecules involved in angiogenesis and lymphangiogenesis, are a controversial subject. Some authors state a significant correlation between expression of VEGF-C and-D and lymphangiogenesis and lymph node status, as well as an increase in the density of blood vessels in tumors (Mohammed et al, 2007; although there are also works in which this relationship is not stated (Currie et al, 2004).…”