NHERF (Na+/H+ Exchanger Regulatory Factor) gene mutations in human breast cancer

Abstract

Yeast two-hybrid screening was used to explore novel proteins that interact with a breast tumor or metastasis suppressor, SYK (spleen tyrosine kinase). The screening yielded NHERF (Na + /H + exchanger regulatory factor, also known as NHERF1 or EBP-50) that binds to the interdomain B of SYK. NHERF is an estrogen-responsive gene that encodes an inhibitory factor for epithelial Na + /H + exchanger isoform 3 (NHE3). We found intragenic mutation of the NHERF gene accompanied by loss of heterzygosity (LOH) in B3% (3/85) of breast cancer cell lines and primary breast tumors. Mutations occurred at the conserved PDZ domains at NHERF NH 2 -terminus that bound to SYK, or at its COOH-terminus motif that binds to MERLIN, the product of Neurofibromatosis 2 (NF2) tumor suppressor gene. NHERF tumorigenic mutations decreased or abolished its interaction with SYK or MERLIN, suggesting a pathway link among these three molecules that may play a critical role in mammary neoplastic progression. Primary breast tumors with LOH at the NHERF locus had clinical presentations of higher aggressiveness, indicating that deregulated NHERF signaling may be associated with disease progression. Moreover, the LOH was inversely correlated with SYK promoter methylation, suggesting that NHERF and SYK may transduce a common suppressive signal. Taken together, the results indicated NHERF to be a candidate tumor suppressor gene in human breast carcinoma that may be interconnected to the SYK and MERLIN suppressors.

Ezrin-anchored Protein Kinase A Coordinates Phosphorylation-dependent Disassembly of a NHERF1 Ternary Complex to Regulate Hormone-sensitive Phosphate Transport

“…Together, these findings introduce a new paradigm for the turnover of PDZ proteins and a novel mechanism by which mutations disrupt the macromolecular assembly and spatiotemporal coordination of hormone action. Such a model may be relevant for elucidating the mechanism whereby other NHERF1 polymorphisms contribute to breast cancer or autoimmune disorders (72,73).…”

Loss of Tumor Suppressor Merlin in Advanced Breast Cancer Is due to Post-translational Regulation

“…In a separate study, Yaegashi et al (20) reported infrequent involvement of mutations in the NF2 gene (encoding for Merlin) in an independent cohort of 60 breast cancer patients. Dai et al (42) reported that the estrogen-response gene and tumor suppressor, Na ϩ /H ϩ exchange regulatory factor (NHERF) likely acts in conjunction with Merlin to transduce a growth suppressive signal. Thus, although there are sporadic references regarding Merlin in breast cancer, the functional and biological roles of Merlin in breast cancer have largely been ignored due to the absence of detectable mutations and the lack of studies of change at the transcript level.…”

Cortical stabilization of β-catenin contributes to NHERF1/EBP50 tumor suppressor function

“…NHERF1 is involved in the regulation of ion transporters and in the trafficking of many transmembrane molecules (Shenolikar et al, 2004), but its role in cancer is still controversial. NHERF1 gene mutations found with low frequency (3%) in breast cancer cell lines and primary tumors were associated with loss of heterozygosity and increased aggressiveness (Dai et al, 2004), suggesting a tumor suppressor role for NHERF1. In contrast, Shibata et al (2003) reported that the NHERF1/b-catenin complex promotes Wnt signaling and may cooperate in the development of liver cancer.…”