Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
Lester and Sue Smith Breast Center, Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Mol Cell Endocrinol. 2018 Aug 15;471:105-117. doi: 10.1016/j.mce.2017.09.024. Epub 2017 Sep 19.
Invasive lobular breast cancer (ILC) is an understudied malignancy with distinct clinical, pathological, and molecular features that distinguish it from the more common invasive ductal carcinoma (IDC). Mounting evidence suggests that estrogen receptor-alpha positive (ER+) ILC has a poor response to Tamoxifen (TAM), but the mechanistic drivers of this are undefined. In the current work, we comprehensively characterize the SUM44/LCCTam ILC cell model system through integrated analysis of gene expression, copy number, and mutation, with the goal of identifying actionable alterations relevant to clinical ILC that can be co-targeted along with ER to improve treatment outcomes. We show that TAM has several distinct effects on the transcriptome of LCCTam cells, that this resistant cell model has acquired copy number alterations and mutations that impinge on MAPK and metabotropic glutamate receptor (GRM/mGluR) signaling networks, and that pharmacological inhibition of either improves or restores the growth-inhibitory actions of endocrine therapy.
浸润性小叶乳腺癌（ILC）是一种研究较少的恶性肿瘤，具有独特的临床、病理和分子特征，与更为常见的浸润性导管癌（IDC）不同。越来越多的证据表明，雌激素受体-α阳性（ER+）的 ILC 对他莫昔芬（TAM）反应不佳，但这种现象的机制驱动因素尚不清楚。在目前的工作中，我们通过综合分析基因表达、拷贝数和突变，对 SUM44/LCCTam ILC 细胞模型系统进行了全面的描述，目的是确定与临床 ILC 相关的可操作改变，这些改变可以与 ER 一起靶向，以改善治疗效果。我们表明，TAM 对 LCCTam 细胞的转录组有几种不同的作用，这种耐药细胞模型获得了影响 MAPK 和代谢型谷氨酸受体（GRM/mGluR）信号网络的拷贝数改变和突变，而抑制其中任何一种都可以改善或恢复内分泌治疗的生长抑制作用。
