Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee Womens Research Institute, Pittsburgh, Pennsylvania.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Endocrinology. 2020 Sep 1;161(9). doi: 10.1210/endocr/bqaa109.
Invasive lobular breast carcinoma (ILC) accounts for 10% to 15% of breast cancers diagnosed annually. Evidence suggests that some aspects of endocrine treatment response might differ between invasive ductal carcinoma (IDC) and ILC, and that patients with ILC have worse long-term survival. We analyzed The Cancer Genome Atlas dataset and observed lower levels of ESR1 mRNA (P = 0.002) and ERα protein (P = 0.038) in ER+ ILC (n = 137) compared to IDC (n = 554), and further confirmed the mRNA difference in a local UPMC cohort (ILC, n = 143; IDC, n = 877; P < 0.005). In both datasets, the correlation between ESR1 mRNA and ERα protein was weaker in ILC, suggesting differential post-transcriptional regulation of ERα. In vitro, 17β-estradiol (E2) decreased the rate of degradation and increased the half-life of ERα in ILC cell lines, whereas the opposite was observed in IDC cell lines. Further, E2 failed to induce robust ubiquitination of ERα in ILC cells. To determine the potential clinical relevance of these findings, we evaluated the effect of 2 selective estrogen receptor downregulators (SERDs), ICI 182,780 and AZD9496, on ERα turnover and cell growth. While ICI 182,780 and AZD9496 showed similar effects in IDC cells, in ILC cell lines, AZD9496 was not as effective as ICI 182,780 in decreasing ERα stability and E2-induced proliferation. Furthermore, AZD9496 exhibited partial agonist activity in growth assays in ILC cell lines. Our study provides evidence for a distinct ERα regulation by SERDs in ILC cell lines, and therefore it is important to include ILC models into preclinical and clinical testing of novel SERDs.
浸润性小叶乳腺癌（ILC）占每年诊断出的乳腺癌的 10%至 15%。有证据表明，内分泌治疗反应的某些方面在浸润性导管癌（IDC）和 ILC 之间可能存在差异，并且 ILC 患者的长期生存情况更差。我们分析了癌症基因组图谱数据集，观察到 ER+ILC（n=137）中 ESR1 mRNA 水平较低（P=0.002），ERα 蛋白水平较低（P=0.038），与 IDC（n=554）相比，并且在当地 UPMC 队列中进一步证实了 mRNA 差异（ILC，n=143；IDC，n=877；P<0.005）。在两个数据集，ILC 中 ESR1 mRNA 和 ERα 蛋白之间的相关性较弱，这表明 ERα 的转录后调控存在差异。在体外，17β-雌二醇（E2）降低了 ILC 细胞系中 ERα 的降解率并增加了 ERα 的半衰期，而在 IDC 细胞系中则观察到相反的情况。此外，E2 未能诱导 ILC 细胞中 ERα 的强烈泛素化。为了确定这些发现的潜在临床相关性，我们评估了两种选择性雌激素受体下调剂（SERDs）ICI 182,780 和 AZD9496 对 ERα 周转和细胞生长的影响。虽然 ICI 182,780 和 AZD9496 在 IDC 细胞中表现出相似的作用，但在 ILC 细胞系中，与 ICI 182,780 相比，AZD9496 在降低 ERα 稳定性和 E2 诱导的增殖方面效果不佳。此外，在 ILC 细胞系中的生长测定中，AZD9496 表现出部分激动剂活性。我们的研究为 SERDs 在 ILC 细胞系中对 ERα 的不同调节提供了证据，因此在新型 SERDs 的临床前和临床测试中纳入 ILC 模型非常重要。
