Center for Clinical and Translational Science, The Rockefeller University, New York, New York, United States of America.
Institut für Formale Methoden der Informatik, Universität Stuttgart, Stuttgart, Germany.
PLoS One. 2018 Jul 2;13(7):e0199012. doi: 10.1371/journal.pone.0199012. eCollection 2018.
Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600-2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance. Results from three independent GWAS of 1000-2000 subjects each, which were made available under the National Institute of Health's "Up For A Challenge" (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of β1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells). Beta-cyclodextrins (βCD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller alpha-cyclodextrins (αCD) also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-αCD to be twice as effective as HPβCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with βCDs are replicated with the safer and more effective αCDs, clinical trials of adjuvant treatment with αCDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HPαCD, but women with triple-negative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.
大多数乳腺癌死亡是由转移引起的，而现有的治疗方法（放疗和细胞毒性药物）有严重的副作用，激素治疗对许多患者已经失效或不再有效，因此迫切需要新的治疗方法。本研究使用一种新的计算生物统计学方法（muGWAS）重新分析了来自三项全基因组关联研究（GWAS）的现有数据，该方法已在 600-2000 例癫痫和自闭症患者的研究中得到验证。muGWAS 联合分析了几个相邻的单核苷酸多态性，同时将遗传性疾病的遗传学知识纳入统计方法，并将 GWAS 纳入确定适应性全基因组显著性的规则中。这三项各自包含 1000-2000 例患者的独立 GWAS 的结果，这些数据是根据美国国立卫生研究院的“Up For A Challenge”（U4C）项目提供的，不仅证实了细胞周期控制和受体/AKT 信号通路，而且首次在乳腺癌 GWAS 中一致鉴定出许多参与内/外排（EEC）的基因，其中大多数已在乳腺癌的功能和表达研究中观察到。特别是，研究结果包括参与进入磷酸肌醇循环的磷脂转运（ATP8A1、ATP8B1、ANO4、ABCA1）和代谢（AGPAT3、AGPAT4、DGKQ、LPPR1）的基因，磷酸肌醇循环控制 EEC。这些新发现表明，清除磷脂可能成为一种新的干预手段，以控制癌症的局部扩散、外泌体的包装（为器官特异性转移准备远处的微环境）以及β1 整合素的内吞作用（这是转移表型扩散和肿瘤细胞间质迁移所必需的）。β-环糊精（βCD）已在乳腺癌的体外和动物研究中显示出有效性，但表现出与胆固醇相关的耳毒性。较小的α-环糊精（αCD）也能清除磷脂，但不能容纳胆固醇。本文介绍的一项体外研究证实，羟丙基（HP）-αCD 对受体阴性和雌激素受体阳性乳腺癌人类细胞的迁移的抑制作用比 HPβCD 强两倍。如果之前用βCD 进行的成功动物研究可以用更安全、更有效的 αCD 复制，那么用 αCD 进行辅助治疗的临床试验是合理的。最终，所有乳腺癌患者都有望从 HPαCD 的治疗中受益，但三阴性乳腺癌（TNBC）患者受益最大，因为她们的治疗选择较少，而且癌症进展更为迅速。
