Mitogen-regulated protein (MRP/PLF; also called proliferin) is a member of the PRL-GH family expressed by the placenta in mid-gestation. This report describes an MRP/PLF receptor in uterine membrane preparations from pregnant mice. Peak receptor activity occurred at 11 days of gestation with a dissociation constant of 6 x 10(-10) M and maximal binding capacity of 86 fmole MRP/PLF/mg membrane protein. PRL, PL-I, and mannose-6-phosphate did not compete for binding, and GH competed weakly only at high concentrations. Primary cells cultured from uteri taken at days 8-11 of gestation responded to MRP/PLF with increases in DNA synthesis. Uterine cells from later stages of gestation did not respond to MRP/PLF. This is the first reported evidence of a function mediated by MRP/PLF and suggests a role for this protein in maternal-fetal interactions during reproduction. Thus, it seems that MRP/PLF is a placentally derived growth factor, which stimulates proliferation in the uterus in a developmentally defined period to coordinate uterine growth with fetal development.

Summary Exposure of ZR-75-1 human breast cancer cells for 48 h to human recombinant interferon alpha (IFNa) 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 10-1OOIUIFNml-l 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 1OIUIFNml-'. 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 (2piM) 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 (10IUml-1) markedly sensitised them to the growth-inhibiting effect of a subsequent 6-day exposure to tamoxifen.

Summary A 6-month exposure of ZR-75-1 human breast cancer cells to tamoxifen (1 UM rising to 2 PM), resulted in a fall in oestrogen receptor (ER) levels from 225 fmol mg protein-1 to 56 fmol mg protein-1 while progesterone receptor (PGR) concentration fell from 63 fmol mg protein-1 to undetectable levels. Sensitivity to the anti-proliferative effects of tamoxifen was unchanged. A further 6 months' exposure to 4 MM tamoxifen resulted in loss of detectable ER and PGR and development of resistance to tamoxifen. Resistant al., 1978). A large subset of ER-positive tumours therefore do not respond, and patients may also relapse following an initial response to the anti-oestrogen. Paradoxically, patients resistant to tamoxifen may respond to alternative hormonal therapy and among patients acquiring 'resistance' to tamoxifen some may show a further response on subsequent re-challenge with the drug.The availability of a number of cell lines derived from human breast cancer has greatly aided studies on the mechanism of oestrogen control of breast cancer cell proliferation and its inhibition by anti-oestrogens. The development of anti-oestrogen resistant variants from such lines should provide further insight into the mechanism of action of and development of resistance to anti-oestrogens. The majority of studies to date have shown that resistance is not associated with the acquisition of an ER-negative phenotype. Thus both the R3 (Nawata et al., 1981b) and R27 (Nawata et al., 1981a) tamoxifen-resistant sub-lines derived from MCF-7 retain ER, although they differ in a number of responses to.oestrogen stimulation. Neither of these lines, however, maintains the resistant phenotype in the absence of continuing tamoxifen exposure (Bronzert et al., 1986). LY2, an MCF-7 variant, was selected for its ability to grow in the presence of the potent anti-oestrogen LY 117018, and is cross-resistant to tamoxifen. This line also expresses ER, although to a lesser extent than MCF-7, and seems to be stably resistant to anti-oestrogens (Bronzert et al., 1985). A tamoxifen and oestrogen insensitive variant of the T47D line, lacking ER but expressing high levels of progesterone receptor (PGR), has also been described but this line arose as a result of changes in culture conditions rather than under selective pressure of anti-oestrogen exposure (Horwitz et al., 1982).In this paper we describe what is, to our knowledge, the first tamoxifen-resistant variant of the ZR-75-1 human breast cancer cell line. This variant arose during prolonged Correspondence: H.W. van den Berg. Received 22 September 1988, and in revised form, 22 October 1988. exposure of the parent line to increasing concentrations of tamoxifen and appears to represent a novel resistant phenotype having lost both ER and PGR. We also describe ultrastructural characteristics of this variant and report on phenotypic stability in the absence of continuing selective pressure. Materials and methodsCell culture and development of the ZR-75-9a1 subline The ZR-75-1 human breast cancer ...

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