How do breast cancers become hormone resistant?
How do breast cancers become hormone resistant?
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乳腺癌如何产生激素抵抗？
DOI：
10.1016/0960-0760(94)90271-2
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Horwitz,KB
中科院分区：
文献类型：
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作者：
Horwitz,KB
我们认为，乳腺肿瘤细胞中雌激素受体(ER)的分子异质性以突变型受体形式的存在为特征，当分析细胞亚群中的孕激素受体(PR)或DNA倍体时，会产生明显的细胞异质性。此外，很可能是细胞的异质性导致对我们所描述的他莫昔芬的反应缺乏一致性。我们发现PR分布和DNA倍体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实质性的重塑。似乎不是“耐药”，而是不同的细胞亚群可以被他莫昔芬抑制或刺激，它们的抑制或生长改变了肿瘤的表型。患者实体瘤中PR的异质性可能预示着对抗雌激素治疗的这种混合的、潜在的危险反应。类似地，由于存在两种正常PR亚型所导致的分子异质性，可能导致某些基因或细胞类型对孕激素拮抗剂的不适当反应。这些激动剂样反应是由于受体和其他转录因子之间的协同作用。随着我们更多地了解肿瘤中PR、ER和其他蛋白质的异质性，我们可能能够识别这种致命的细胞亚群，或调控因子的组合。具体地说，关于他莫昔芬，我们的数据表明，它被用作乳腺癌高危女性的化学预防药物[Kiang，J.Natn。癌症研究所。83,1991,462-463]应谨慎看待，因为在他莫昔芬存在的情况下，可能会出现被药物刺激而不是抑制的细胞亚群。
We propose that the molecular heterogeneity of estrogen receptors (ER) in breast tumor cells characterized by the presence of mutant receptor forms, generates the cellular heterogeneity evident when progesterone receptor (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 that we have described. We find that heterogeneity of PR distribution and DNA ploidy reflects the 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 agonist-like 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, with respect to tamoxifen, our data suggest that its use as a chemopreventant in women at high risk of developing breast cancer [Kiang, J. Natn. Cancer Inst. 83, 1991, 462–463] 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.