Functional Biomorphology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy.
PLoS One. 2013;8(1):e53070. doi: 10.1371/journal.pone.0053070. Epub 2013 Jan 11.
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.
血管生成在乳腺癌的生长和进展中起着重要作用，其受到促血管生成和抗血管生成因子之间的平衡调节。在缺氧条件下，缺氧诱导因子-1α（HIF-1α）会使血管内皮生长因子（VEGF）的表达上调。已知 HIF-1α 与 BRCA1 携带者癌症之间存在相互作用，但有关 BRCA1-2 携带者和 BRCAX 乳腺癌中的血管生成的报道甚少。在这项研究中，我们通过免疫组织化学方法检测了 26 例 BRCA1-2 携带者和 58 例 BRCAX 与 77 例散发性乳腺癌中 VEGF 和 HIF-1α 的表达和微血管密度（MVD）。BRCA1-2 携带者中的 VEGF 表达高于 BRCAX 癌组织（p=0.0001）。此外，BRCA1-2 携带者和 BRCAX 中的 VEGF 表达均高于散发性组（p<0.0001）。VEGF 免疫反应性与肿瘤分级差（p=0.0074）、激素受体阴性（p=0.0206，p=0.0002）和 MIB-1 标记指数（p=0.0044）相关（家族性癌症，BRCA1-2 和 BRCAX）。BRCA1-2 携带者中核 HIF-1α 的表达百分比高于 BRCAX 癌症（p<0.05），并且在所有家族性肿瘤中均高于散发性肿瘤（p=0.0045）。BRCA1-2 携带者中的 MVD 高于 BRCAX 和散发性癌组织（p=0.002，p=0.0001），并且在所有家族性肿瘤中均高于散发性肿瘤（p=0.01）。在 BRCA1-2 携带者中，MVD 与 HIF-1α 表达呈正相关（r=0.521，p=0.006），特别是在家族性组中，相关性非常显著（r=0.421，p<0.0001）。我们的发现表明，血管生成在 BRCA1-2 携带者乳腺癌中起着至关重要的作用。需要对更大的 BRCA1-2 携带者系列进行前瞻性研究，以改善针对该亚组乳腺癌患者的最佳治疗策略。
