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.
Highlights
Breast cancer continues to be the leading cause of morbidity and mortality in European women [1]
Cytoplasmic vascular endothelial growth factor (VEGF) expression was observed in 95% (153/161) of breast cancers, and it was positive in 59% (91/153) of tumor
No significant difference in hypoxia-inducible factor-1a (HIF-1a) expression was present between the BRCAX and the sporadic group (Fig. 4A)
Summary
Breast cancer continues to be the leading cause of morbidity and mortality in European women [1]. 7% of all breast cancers present a familial breast cancer history, and around 25% of these have germline mutations in BRCA1 and BRCA2 genes [2,3]. Family history of breast cancer remains a predictive risk factor, after carrier status for BRCA1 and/or BRCA2 mutations has been investigated. There are more of 1,500 distinct mutations, polymorphisms and variants in BRCA1-2 genes, among which small frame shift insertions, deletions, non-sense mutations etc [4]. Both BRCA genes are involved in the repair of damaged DNA and both function in common pathway that is responsible for the integrity of the genome [5]. Other than BRCA1-2 genes, mutations in different autosomal dominant genes with high or moderate penetrance breast cancer susceptibility (such as TP53, ATM, RAD50, PTEN) can be found and defined BRCAX [7]
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