Cellular heterogeneity and mutant oestrogen receptors in hormone resistant breast cancer.

In summary, we propose that the molecular heterogeneity of ER in breast tumour cells, characterized by the presence of mutant receptor forms, generates the cellular heterogeneity evident when PR or DNA ploidy are analysed in cell subpopulations. Furthermore, it is likely that cellular heterogeneity leads to the lack of uniformity in response to tamoxifen that we have described. We find that heterogeneity of PR and DNA ploidy reflects the existence of mixed subpopulations of breast cancer cells that are substantially remodelled under the influence of tamoxifen. It appears likely that different subsets of cells, rather than being "resistant", can be inhibited or stimulated by tamoxifen and that their suppression or outgrowth alters the phenotype of the tumour. PR heterogeneity in solid tumours of patients may predict a mixed, and potentially dangerous, response to anti-oestrogen treatment. As we learn more about the heterogeneity of PR, ER and other proteins in tumours, we may be able to recognize such lethal subpopulations, which the flow cytometry immunoassay can simply and rapidly measure. Our data also suggest that the use of tamoxifen as a chemopreventant in women at high risk of developing breast cancer (Kiang, 1991) should be viewed with caution.