Summary Xenograft tumours from an oestrogen-dependent human breast cancer cell line MCF-7 have been established and characterised in thymectomised, irradiated female CBA strain mice. There was evidence for selection in xenografts of a subpopulation of MCF-7 cells with an altered pattern of gene expression as measured by mRNA levels compared with the original cells in vitro. Tumorigenicity increased significantly on repeated animal passage but oestrogen dependence was retained. Following injection of the mice with oestrogen, mitosis was induced in the tumour cells with associated increases in thymidine uptake and percentage of cells in S-phase. In accord with these changes, c-myc and p53 expression were increased and TGF-beta was suppressed. Thereafter the expression of the c-myc and p53 genes fell whilst that of the TGF-beta gene was induced-as the oestrogenic stimulus declined. The oestrogen-regulated mRNA pS2 showed a biphasic response to oestrogen and levels declined as the serum oestrogen fell to undetectable levels. This xenograft system demonstrates that changes in transcription of oncogenes, growth factor and oestrogenregulated genes can be detected in vivo in response to oestrogen. It thus provides an in vivo model for studies of the biochemical and molecular basis for therapeutic manipulation of hormone-sensitive human breast cancer.In studying the molecular biology of cancer cells, the significance of in vitro observations may be uncertain due to the absence of host factors that influence tumour behaviour in vivo. Recent work on experimental human breast tumours in vivo has made use, almost exclusively, of congenitally athymic ('nude') mice Brunner et al., 1989). We have previously reported the growth of a range of human tumours in thymectomised, irradiated mice (Busuttil et al., 1986) which have advantages in ease of husbandry and cost (Steel et al., 1978;Morten et al., 1984;Hay et al., 1985). We report here the characterization of an oestrogenresponsive tumour derived from the MCF-7 human breast carcinoma cell line grown in vivo in female thymectomised and irradiated CBA mice. In addition, we have examined the kinetics of the expression of a range of related genes (c-myc, p53, TGF-beta and pS2) following oestrogenic stimulation in this tumour model system.
Materials and methods
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