Aim: 

The Na+/H+ exchanger regulatory factor (NHERF1) is a PDZ domain-containing scaffolding protein that recruits membrane receptors/transporters and cytoplasmic signaling proteins into functional complexes. We have reported that NHERF1 expression in human biopsies of breast cancer correlates with aggressive clinical characteristics and poor prognosis.

Methods: 

We stably transfected a metastatic breast cell line, MDA-MB-231, with the pcDNA 3.1/Higro empty vector, with wildtype (wt) NHERF1 or with NHERF1 mutated in either the PDZ1 (HRF1) or PDZ2 (HRF2) domains and tested these clones for their ability to affect growth and metastasis both in vitro and in vivo.

Results: 

Anchorage-independent growth and in vivo tumor formation are reduced upon over-expression of NHERF1 via the action of mainly the PDZ1 domain. Experiments conducted in three-dimensional cultures followed by 3D microscopical optical sectioning demonstrate that the PDZ2 domain of NHERF1 induces both invadopodium formation and invadopodial-dependent extracellular matrix (ECM) digestion, while it negatively regulates the vasculogenic ability of breast cancer cells. In BALB/c-nu/nu mice subjected to intracardiac injection of NHERF1 over-expressing cells, expression of the dominant negative PDZ1 mutation of NHERF1 increased visceral metastases while that of the dominant negative PDZ2 mutation increased bone metastases.

Conclusion: 

We propose that NHERF1 can differently reprogram the tumor progression phenotype by specific loss of function of its PDZ domains.