Horwitz K B
University of Colorado Health Sciences Center, Denver 80262.
Prog Clin Biol Res. 1994;387:29-45.
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.
我们提出，乳腺肿瘤细胞中雌激素受体（ER）的分子异质性（其特征为存在突变受体形式）产生了细胞异质性，这在对细胞亚群进行孕激素受体（PR）或DNA倍性分析时很明显。此外，细胞异质性很可能导致对他莫昔芬反应缺乏一致性。我们发现PR分布和DNA倍性的异质性反映了乳腺癌细胞混合亚群的存在，这些亚群在他莫昔芬的影响下发生了显著重塑。看起来细胞的不同亚群并非“耐药”，而是可能被他莫昔芬抑制或刺激，它们的受抑制或生长会改变肿瘤的表型。患者实体瘤中的PR异质性可能预示着对抗雌激素治疗的这种混合且潜在危险的反应。同样，由两种正常PR同种型的存在导致的分子异质性可导致某些基因或细胞类型对孕激素拮抗剂产生不适当反应。这些激动剂样反应是由于受体与其他转录因子之间的协同相互作用。随着我们对肿瘤中PR、ER和其他蛋白质的异质性了解得更多，我们或许能够识别出此类致命的细胞亚群或调节因子组合。具体而言，就他莫昔芬而言，我们的数据表明，鉴于在他莫昔芬存在的情况下可能会出现被该药物刺激而非抑制的细胞亚群，在乳腺癌高危女性中（Kiang，1991）将其用作化学预防剂时应谨慎看待。
