Recombinant human interferon alpha increases oestrogen receptor expression in human breast cancer cells (ZR-75-1) and sensitizes them to the anti-proliferative effects of tamoxifen.

Hw Van Den Berg,J Nelson,M Lynch,R Clarke,Wj Leahey

doi:10.1038/bjc.1987.49

Abstract

Exposure of ZR-75-1 human breast cancer cells for 48 h to human recombinant interferon alpha (IFN alpha) resulted in increased expression of oestrogen receptors as measured in a whole cell binding assay. This effect was inversely proportional to dose being significant following treatment with 10-100 IU IFN ml-1 and was only observed at a low initial cell plating density. The extent of the increase in oestrogen receptor levels ranged from 1.2- to 7.2-fold following treatment with 10 IU IFN ml-1. No increase in progesterone receptor expression was observed under the same experimental conditions. Concentrations of IFN which increased oestrogen receptor levels had no effect on cell proliferation. IFN (500 IU ml-1) inhibited cell proliferation and the combination of this treatment with tamoxifen (2 microM) had a greater anti-proliferative effect than either drug alone although there was no evidence of synergism. However, a 5-day pretreatment of cells with IFN (10 IU ml-1) markedly sensitised them to the growth-inhibiting effect of a subsequent 6-day exposure to tamoxifen.

Highlights

In this paper we have extended our earlier observations and report that IFNac 2 increases ER but not PGR expression in the ZR-75-1 human breast cancer cell line and that the effect on detectable ER is inversely proportional to dose and dependent on cell plating density
Cell proliferation was inhibited in cells continually exposed to 500 IUml-1 IFN and the combination of this concentration of IFN and 2pM tamoxifen was more growth inhibitory than either drug alone but again there was no evidence of synergism
We have demonstrated that interferon alpha (IFNa) increases ER expression in the ZR-75-1 human breast cancer cell line

Summary

Methods

The ZR-75-1 human breast cancer line was obtained from Flow Laboratories (Irvine, Scotland) and its human and mammary origin has been described previously (Lippman et al, 1977). ER and PGR expression were determined using a whole cell binding assay at 37°C similar to that described by OleaSerrano et al (1985). The medium was removed and oestrogen or progesterone binding assessed using either a single concentration of ligand (I nM) or a range of concentrations for determination of maximal binding capacity (Bmax) and dissociation constant (Kd). 140 Cimmol- 1, Amersham International plc) as the radioactive ligand (0.25-3.5nM) in the absence or presence of a 200-fold excess of diethylstilbestrol. Lines were fitted by linear regression analysis and standard deviations associated with the derived parameters estimated, (Davies & Goldsmith 1972)

Results

Discussion

Conclusion