Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.

中文翻译：

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由外源雌激素引起的小鼠 ER+/PIK3CAH1047R 乳腺癌对雌激素具有异质依赖性，并在 BH3 和 PI3K 药物的作用下经历 BIM 依赖性细胞凋亡。

雌激素依赖是 ER + 乳腺癌的主要驱动因素，这与 PI3K 突变有关。PI3K 抑制 (PI3Ki) 可以恢复某些激素治疗耐药的 ER + 乳腺癌对 ER 信号传导的依赖，但对其他乳腺癌无效。在这里，我们表明，短期补充雌激素可强烈增强 Pik3caH1047R 诱导的小鼠乳腺肿瘤发生，仅导致 ER + 肿瘤，证明激素和癌基因在肿瘤发展中的协同作用。与诊断时内分泌依赖性或内分泌非依赖性的人类 ER + 乳腺癌类似，该模型的肿瘤系保留了 ER 表达，但对激素治疗敏感或耐药。PI3Ki 不会诱导细胞死亡，但会导致促凋亡基因 BIM 上调。BH3 模拟物或 PI3Ki 无法恢复几种耐药小鼠和人类肿瘤系的激素敏感性。然而重要的是，PI3Ki 和 BH3 模拟物的组合对 PIK3CA 突变癌细胞具有深远的、BIM 依赖性细胞毒性作用，同时不影响正常细胞。我们提出，添加 BH3 模拟物提供了一种治疗策略，可显着提高 PI3Ki 在激素治疗耐药和 ER 独立的 PIK3CA 突变乳腺癌中的细胞毒活性。