Royal Marsden Hospital, Institute of Cancer Research, London, United Kingdom.
Clin Cancer Res. 2010 Mar 1;16(5):1486-97. doi: 10.1158/1078-0432.CCR-09-1764. Epub 2010 Feb 23.
Acquired endocrine resistance in estrogen receptor (ER)alpha+/human epidermal growth factor receptor 2-negative (HER2-) breast cancer has been associated with modest adaptive increases in HER2, although exactly how aberrant HER2 signaling affects the ERalpha pathway is poorly understood. We investigated (a) whether the epidermal growth factor receptor/HER2 inhibitor lapatinib could restore endocrine responsiveness in cell models of acquired endocrine resistance with modest increases in HER2, and (b) the nature of ERalpha-HER2 cross-talk in this process.
Combination growth studies, ERalpha transcription, immunoblot, and gene expression assays were conducted in two models of acquired resistance to (a) estrogen deprivation (long-term estrogen-deprived cells) and (b) tamoxifen (long-term tamoxifen-treated cells), and in hormone sensitive controls. Changes in ERalpha, PgR, and HER2 were assessed in samples from patients treated with tamoxifen.
Both cell models of acquired endocrine resistance showed modest adaptive upregulation in HER2, and lapatinib restored endocrine sensitivity in both. The effect of lapatinib on ERalpha signaling varied markedly depending on the nature of the HER2/ERalpha cross-talk. In long-term estrogen-deprived cells characterized by enhanced ERalpha function, lapatinib suppressed ERalpha genomic activity (as measured by pERSer118, ERalpha transcriptional activity, and PGR gene expression). In contrast, in long-term tamoxifen-treated cells with reduced ERalpha activation, lapatinib reactivated ERalpha genomic function. Twenty percent of tamoxifen-resistant patients relapsed with modest increases in HER2 and either suppressed or enhanced ERalpha/PgR expression.
Aberrant GFR signaling can augment or suppress ERalpha function. Regardless, interrupting the HER2/ERalpha cross-talk with lapatinib can restore endocrine sensitivity and should be investigated as a therapeutic strategy in combination with endocrine therapy in ERalpha+/HER2- patients with acquired endocrine resistance.
在雌激素受体 (ER)alpha+/人表皮生长因子受体 2 阴性 (HER2-) 乳腺癌中获得的内分泌抵抗与 HER2 的适度适应性增加有关，尽管异常的 HER2 信号如何影响 ERalpha 途径尚不清楚。我们研究了 (a) 在 HER2 适度增加的获得性内分泌抵抗的细胞模型中，表皮生长因子受体/HER2 抑制剂拉帕替尼是否可以恢复内分泌反应性，以及 (b) 在这个过程中 ERalpha-HER2 交叉对话的性质。
在两种获得性抵抗雌激素剥夺（长期雌激素剥夺细胞）和 (b) 他莫昔芬（长期他莫昔芬治疗细胞）的模型中以及在激素敏感对照中进行了联合生长研究、ERalpha 转录、免疫印迹和基因表达测定。评估了接受他莫昔芬治疗的患者样本中 ERalpha、PgR 和 HER2 的变化。
两种获得性内分泌抵抗的细胞模型均显示 HER2 的适度适应性上调，拉帕替尼恢复了两者的内分泌敏感性。拉帕替尼对 ERalpha 信号转导的影响因 HER2/ERalpha 交叉对话的性质而异。在以增强的 ERalpha 功能为特征的长期雌激素剥夺细胞中，拉帕替尼抑制 ERalpha 基因组活性（如通过 pERSer118、ERalpha 转录活性和 PGR 基因表达测量）。相比之下，在 ERalpha 激活减少的长期他莫昔芬治疗细胞中，拉帕替尼重新激活了 ERalpha 基因组功能。20%的他莫昔芬耐药患者出现 HER2 适度增加，并伴有 ERalpha/PgR 表达抑制或增强。
异常的 GFR 信号可以增强或抑制 ERalpha 功能。无论如何，用拉帕替尼中断 HER2/ERalpha 交叉对话可以恢复内分泌敏感性，并且应该在 ERalpha+/HER2-获得性内分泌抵抗患者中与内分泌治疗联合作为一种治疗策略进行研究。
