NHERF1 together with PARP1 and BRCA1 expression as a new potential biomarker to stratify breast cancer patients.

Anita Mangia,Francesco Giotta,Laura Schirosi,Emanuela Scarpi,Giuseppina Opinto,Giovanni Simone,Giulia Partipilo

doi:10.18632/oncotarget.19444

Abstract

It has been recognized that Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) in breast cancer (BC) acts as a tumor suppressor or as an oncogenic protein, depending on its subcellular localization. This study aims to correlate NHERF1 expression to BRCA1 and PARP1 proteins, to investigate their relationship, and their biological and clinical significance. Using immunohistochemistry on tissue microarrays, we evaluated subcellular NHERF1, BRCA1 and PARP1 expression in 308 BCs including a subgroup (n=80) of triple negative BCs (TNBCs). Herein, we show that nuclear NHERF1 (nNHERF1) expression was significantly associated with nuclear BRCA1 (nBRCA1) expression (p=0.0008), and an association was also found between nuclear PARP1 (nPARP1) and nBRCA1 (p<0.0001). Cytoplasmic NHERF1 (cNHERF1) was correlated to nPARP1 (p<0.0001). Survival analyses showed that the patients with positive nPARP1 and nNHERF1 tended toward a shorter 5-year overall survival (OS) (p=0.057). In TNBCs, the association between nBRCA1 and nPARP1 was maintained (p<0.0001), and an association between nNHERF1 and nPARP1 was observed (p=0.010). Univariate analysis revealed that TNBCs with positive cNHERF1 and nPARP1 had a shorter 5-year OS (p=0.048).Our data suggest that NHERF1 could be a new potential biomarker in combination with PARP1 and BRCA1 expression to stratify BC patients. In particular, in TNBCs, cNHERF1 associated with nPARP1 expression identified a patient subgroup with a shorter survival, for whom it may be useful to develop novel therapeutic strategies.

Highlights

Breast cancer (BC) remains the most common malignancy in women in many countries [1] and is the leading cause of cancer death, despite great advances in early diagnosis and treatments
We show that nuclear Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) expression was significantly associated with nuclear BRCA1 expression (p=0.0008), and an association was found between nuclear Poly[ADPRibose] Polymerase 1 (PARP1) and nBRCA1 (p
We examined the subcellular expression of NHERF1, BRCA1 and PARP1 proteins in invasive breast carcinomas and investigated, for the first time, the relationship among their expression and with patient outcome

Summary

Introduction

Breast cancer (BC) remains the most common malignancy in women in many countries [1] and is the leading cause of cancer death, despite great advances in early diagnosis and treatments. Understanding the expression of the molecules involved in cell signaling, control of cell growth, DNA repair and death, could www.impactjournals.com/oncotarget improve knowledge of the pathways that contribute to the cancerogenesis, tumor differentiation and progression of breast cancer. The expression and different subcellular distribution of NHERF1 (from the apical membrane to the cytoplasm or nucleus) is compatible with its dual role [18, 19]. We observed that the progressive cytoplasmic NHERF1 overexpression and the decrease of membranous NHERF1 expression were related to BC development and progression, suggesting an important role for this protein during the carcinogenesis [19]. The knowledge of the damaged pathway can help to understand the interaction between the various DNA repair systems and to find potential candidate targets for selective therapy

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