VEGF, HIF-1α expression and MVD as an angiogenic network in familial breast cancer

Abstract

Angiogenesis, which plays an important role in tumor growth and progression of breast cancer, is regulated by a balance between pro- and anti-angiogenic factors. Expression of vascular endothelial growth factor (VEGF) is up-regulated during hypoxia by hypoxia-inducible factor-1α (HIF-1α). It is known that there is an interaction between HIF-1α and BRCA1 carrier cancers, but little has been reported about angiogenesis in BRCA1-2 carrier and BRCAX breast cancers. In this study, we investigated the expression of VEGF and HIF-1α and microvessel density (MVD) in 26 BRCA1-2 carriers and 58 BRCAX compared to 77 sporadic breast cancers, by immunohistochemistry. VEGF expression in BRCA1-2 carriers was higher than in BRCAX cancer tissues (p = 0.0001). Furthermore, VEGF expression was higher in both BRCA1-2 carriers and BRCAX than the sporadic group (p<0.0001). VEGF immunoreactivity was correlated with poor tumor grade (p = 0.0074), hormone receptors negativity (p = 0.0206, p = 0.0002 respectively), and MIB-1-labeling index (p = 0.0044) in familial cancers (BRCA1-2 and BRCAX). The percentage of nuclear HIF-1α expression was higher in the BRCA1-2 carriers than in BRCAX cancers (p<0.05), and in all familial than in sporadic tumor tissues (p = 0.0045). A higher MVD was observed in BRCA1-2 carrier than in BRCAX and sporadic cancer tissues (p = 0.002, p = 0.0001 respectively), and in all familial tumors than in sporadic tumors (p = 0.01). MVD was positively related to HIF-1α expression in BRCA1-2 carriers (r = 0.521, p = 0.006), and, in particular, we observed a highly significant correlation in the familial group (r = 0.421, p<0.0001). Our findings suggest that angiogenesis plays a crucial role in BRCA1-2 carrier breast cancers. Prospective studies in larger BRCA1-2 carrier series are needed to improve the best therapeutic strategies for this subgroup of breast cancer patients.

Figure 1. Cytoplasmic immunoreactivity of VEGF in representative tissue samples of breast cancer.

(A) and (B) show VEGF overexpression in BRCA1-2 carrier and BRCAX breast cancers respectively; (C) shows low expression of VEGF in sporadic breast cancers.

Figure 2. VEGF protein expression detected in different breast cancer groups.

(A) VEGF expression was significantly higher in BRCA1-2 carriers than in BRCAX and sporadic group; further, VEGF expression was significantly higher in BRCAX than in sporadic cancers; (B) VEGF expression was more intensive in all familial than in sporadic cancers. *** = p≤0.0001.

Figure 3. Nuclear immunoreactivity of HIF-1α in representative tissue samples of breast cancer.

(A) and (B) show nuclear HIF-1α overexpression in BRCA1-2 carrier and BRCAX breast cancers respectively; (C) shows low nuclear HIF-1α expression in sporadic breast cancers.

Figure 4. HIF-1α protein expression detected in different breast cancer groups.

(A) Nuclear HIF-1α expression was significantly higher in BRCA1-2 carriers than in BRCAX and sporadic group; (B) Nuclear HIF-1α expression was more intensive in all familial than in sporadic cancers. * = p<0.05; ** = p<0.01; *** = p≤0.0001.

Figure 5. Microvessel density in representative tissue samples of breast cancer.

(A) and (B) show high MVD in BRCA1-2 carrier and BRCAX breast cancers respectively; (C) shows low MVD in sporadic breast cancers.

Figure 6. Microvessel density detected in different breast cancer groups.

(A) MVD was significantly higher in BRCA1-2 carriers than in BRCAX and sporadic group; (B) MVD was more intensive in all familial than in sporadic cancers. * = p<0.05; ** = p<0.01; *** = p≤0.0001.