We propose that the molecular heterogeneity of ER in breast tumor cells characterized by the presence of mutant receptor forms generates the cellular heterogeneity evident when PR or DNA ploidy are analyzed in cell subpopulations. Furthermore, it is likely that cellular heterogeneity leads to the lack of uniformity in response to tamoxifen. We find that heterogeneity of PR distribution and DNA ploidy reflects existence of mixed subpopulations of breast cancer cells that are substantially remodeled under the influence of tamoxifen. It appears likely that rather than being "resistant, "different subsets of cells can be inhibited or stimulated by tamoxifen, and their suppression or outgrowth alters the phenotype of the tumor. PR heterogeneity in solid tumors of patients may predict for such a mixed, and potentially dangerous, response to antiestrogen treatment. Similarly, the molecular heterogeneity resulting from the presence of two normal PR isotypes can lead to inappropriate responses to progesterone antagonists in certain genes or cell types. These agonistlike responses are due to cooperative interactions between the receptors and other transcription factors. As we learn more about the heterogeneity of PR, ER, and other proteins in tumors, we may be able to recognize such lethal cell subpopulations or combinations of regulatory factors. Specifically, our data suggest, with respect to tamoxifen, that its use as a chemopreventant in women at high risk of developing breast cancer (Kiang 1991) should be viewed with caution, since in the presence of tamoxifen, subpopulations of cells may arise that are stimulated, rather than inhibited, by the drug.