Abstract
Familial breast cancer (BC) is a heterogeneous disease with variable prognosis. The identification of an immunoprofile is important to predict tumor behavior for the routine clinical management of familial BC patients. Using immunohistochemistry on tissue microarrays, we studied 95 familial BCs in order to analyze the expression of some biomarkers involved in different pathways. We used unsupervised hierarchical clustering analyses (HCA), performed using the immunohistochemical score data, to define an immunoprofile able to characterize these tumors. The analyses on 95 and then on a subset of 45 tumors with all biomarkers contemporarily evaluable, revealed the same biomarker and patient clusters. Focusing on the 45 tumors we identified a group of patients characterized by the low expression of estrogen receptor (P = 0.009), progesterone receptor (P < 0.001), BRCA1 (P = 0.005), nuclear Na+/H+ exchanger regulatory factor 1 (NHERF1) (P = 0.026) and hypoxia inducible factor-1 alpha (P < 0.001), and also by the higher expression of MIB1 (P = 0.043), cytoplasmic NHERF1 (P = 0.004), cytoplasmic BRCT-repeat inhibitor of hTERT expression (P = 0.001), vascular endothelial growth factor (VEGF) (P = 0.024) and VEGF receptor-1 (P = 0.029). This immunoprofile identified a more aggressive tumor phenotype associated also with a larger tumor size (P = 0.012) and G3 grade (P = 0.006), confirmed by univariate and multivariate analyses. In conclusion, the clinical application of HCA of immunohistochemical data could allow the assessment of prognostic biomarkers to be used simultaneously. The 10 protein expression panel might be used to identify the more aggressive tumor phenotype in familial BC and to direct patients towards a different clinical therapy.
Highlights
Breast cancer (BC) is the most frequent malignant disease, and the leading cause of cancer death among women
Using IHC on tissue microarrays (TMAs), we have focused on familial breast tumors in order to analyze the expression of different biomarkers involved in some pathways: progression (NHERF1, TWIST1, Claudin 1), DNA repair mechanisms (BRCT-repeat inhibitor of hTERT expression (BRIT1), SWItch 5 (SWI5), breast cancer susceptibility gene-1 (BRCA1) and Poly [ADP-ribose] polymerase 1 (PARP1)), angiogenesis (vascular endothelial growth factor receptor 1 (VEGFR1), VEGF, HIF-1α and microvessel density (MVD)), and breast staminal cell markers (CD44 and CD24)
The frequency of the immunohistochemical expression of Na+/H+ exchanger regulatory factor 1 (NHERF1), TWIST1, Claudin 1, BRIT1, SWI5, BRCA1, PARP1, VEGFR1, VEGF, HIF-1α, MVD, CD44 and CD24 was evaluated on TMAs containing 285 specimens from 95 familial BC patients
Summary
Breast cancer (BC) is the most frequent malignant disease, and the leading cause of cancer death among women. Instead, been performed in order to characterize a set of immunohistochemical and pathological markers that could help to distinguish the non-BRCA1/2 familial tumors from the familial cancers carrying these gene mutations, demonstrating the heterogeneity of familial BC [2, 17]. Given this heterogeneity and the variability in the clinical progression of disease, the identification of a set of biomarkers, rather than a single one, seems to be important to predict tumor behavior for the clinical management of patients and to develop new treatment modalities [18, 19]
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