Estrogen receptor prevents p53-dependent apoptosis in breast cancer
Estrogen receptor prevents p53-dependent apoptosis in breast cancer
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DOI：
10.1073/pnas.1018858109
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发表时间：
2012-10-30
影响因子：
11.1
通讯作者：
Brown, Myles
中科院分区：
文献类型：
--
作者：
Bailey, Shannon T.;Shin, Hyunjin;Brown, Myles
超过三分之二的乳腺癌表达雌激素受体（ER），并依赖雌激素生长和生存。针对内质网功能的治疗，包括阻断雌激素产生的芳香化酶抑制剂和改变内质网转录活性的内质网拮抗剂，在治疗所有阶段的内质网阳性乳腺癌中发挥着核心作用。与雌激素受体乳腺癌不同，雌激素受体乳腺癌经常携带p53肿瘤抑制因子突变，而雌激素受体乳腺癌主要是p53的野生型。尽管含有野生型p53， ER+乳腺癌细胞在雌激素存在下对化疗诱导的凋亡具有抗性。使用全基因组方法，我们已经解决了内质网拮抗p53促凋亡功能的机制。有趣的是，雌激素受体激动剂如雌二醇和选择性雌激素受体调节剂（SERM）他莫昔芬都能促进p53的拮抗作用。相反，全内质网拮抗剂氟维司汀阻断内质网抑制p53介导的细胞死亡的能力。这种抑制作用通过一种机制起作用，该机制涉及p53和ER靶基因的一个亚群的调节，可以预测ER+乳腺癌患者的无复发生存。这些发现表明，使用完全阻断ER作用的拮抗剂和激活p53介导的细胞死亡的药物，可以改善治疗ER+乳腺癌的策略。
More than two-thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function, including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity, play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER- breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild type for p53. Despite harboring wild-type p53, ER+ breast cancer cells are resistant to chemotherapy-induced apoptosis in the presence of estrogen. Using genome-wide approaches, we have addressed the mechanism by which ER antagonizes the proapoptotic function of p53. Interestingly, both ER agonists such as estradiol and the selective ER modulator (SERM) tamoxifen promote p53 antagonism. In contrast, the full ER antagonist fulvestrant blocks the ability of ER to inhibit p53-mediated cell death. This inhibition works through a mechanism involving the modulation of a subset of p53 and ER target genes that can predict the relapse-free survival of patients with ER+ breast cancer. These findings suggest an improved strategy for the treatment of ER+ breast cancer using antagonists that completely block ER action together with drugs that activate p53-mediated cell death.