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Na + /H +  exchanger regulatory factor 1  (NHERF1 , also known as  EBP50  or  NHERF ) is a putative tumour suppressor gene in human breast cancer. Located at  17q25.1 ,  NHERF1  is frequently targeted during breast tumourigenesis. Loss of heterozygosity (LOH) at the  NHERF1  locus is found in more than 50% of breast tumours. In addition,  NHERF1  is mutated in a subset of primary breast tumours and breast cancer cell lines. LOH at the  NHERF1  locus is strongly associated with aggressive features of breast tumours, implicating  NHERF1  as a haploinsufficiency tumour suppressor gene. However, the putative NHERF1 tumour suppressor activity has not been functionally verified.    Methods  To confirm the NHERF1 tumour suppressor activity suggested by our genetic analyses, we used retrovirus-transduced short hairpin RNA (shRNA) to knock down NHERF1 expression in breast cancer cell lines MCF7 and T47D. These cells were then assessed for cell growth  in vitro  and  in vivo . The control and NHERF1 knockdown cells were also serum-starved and re-fed to compare their cell cycle progression as measured by fluorescence-activated cell sorting analyses.    Results  We found that downregulation of the endogenous NHERF1 in T47D or MCF7 cells resulted in enhanced cell proliferation in both anchorage-dependent and -independent conditions compared with that of the vector control cells. NHERF1 knockdown T47D cells implanted at mammary fat pads of athymic mice formed larger tumours than did control cells. We found that serum-starved NHERF1 knockdown cells had a faster G 1 -to-S transition after serum re-stimulation than the control cells. Immunoblotting showed that the accelerated cell cycle progression in NHERF1 knockdown cells was accompanied by increased expression of cyclin E and elevated Rb phosphorylation level.    Conclusion  Our findings suggested that the normal NHERF1 function in mammary epithelial cells involves blockage of cell cycle progression. Our study affirmed the tumour suppressor activity of NHERF1 in breast which may be related to its regulatory effect on cell cycle. It warrants future investigation of this novel tumour suppressor pathway in human breast cancer which may turn up therapeutic opportunities.

Suppression of breast cancer cell growth by Na+/H+ exchanger regulatory factor 1 (NHERF1)