NHERF1/EBP50 in Breast Cancer: Clinical Perspectives

Abstract

Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) is a postsynaptic density 95/disc-large/zona occludens (PDZ) domain-containing protein that recruits membrane receptors/transporters and cytoplasmic signaling proteins into functional complexes. NHERF1 expression has been demonstrated to be altered in breast cancer, but its role in mammary cancerogenesis and progression remains still undefined. In this paper, we review what is known on the pathological role and the potential clinical application of NHERF1 protein in breast cancer. Recent evidence shows that an increased cytoplasmic expression of NHERF1 suggests a key role of its localization/compartmentalization in defining cancerogenesis, progression, and invasion. NHERF1 overexpression is associated with increasing tumor cytohistological grade, aggressive clinical behavior, unfavorable prognosis, and increased tumor hypoxia. Moreover, NHERF1 co-localizes with the oncogenic receptor HER2/neu in HER2/neu-overexpressing carcinoma and in distant metastases. These data make NHERF1 also a potential candidate of clinical relevance for anti-HER2/neu therapy.

Fig. 1

Cellular distribution of NHERF1 in breast tissues. Cytoplasmic/membranous NHERF1 protein expression ratio evaluated in normal breast tissue, carcinoma in situ, invasive tumor, synchronous metastatic lymph nodes, and metachronous distant metastasis tissues (horizontal bold line in the box marks mean value; ∗∗∗p < 0.0001, ∗∗p < 0.001, ∗p < 0.01, by parametric unpaired t-test).

Fig. 2

Immunohistochemical analysis of NHERF1 protein in breast cancer. NHERF1 expression in A morphologically normal tissue is present as apical membranous reactivity; B in carcinoma in situ NHERF1 immunoreactivity is localized in the cytoplasmic subcellular compartment and in the membrane of subluminal cells; C in invasive tumor NHERF1 is present as cytoplasmic staining (original magnification ×400).