近日，美国洛克菲勒大学教授Sohail F. Tavazoie及其课题组发现，一种常见遗传性人类PCSK9种系变异通过LRP1受体驱动乳腺癌转移。2024年12月9日，《细胞》杂志在线发表了这项成果。
研究人员表示，识别有转移性复发风险的患者是一个重要的医学需求。研究人员发现了前蛋白转化酶亚家族成员9（PCSK9）中的一种常见错义种系变异（rs562556，V474I），该变异与多组乳腺癌患者的生存期缩短相关。
在小鼠中对这一功能获得型单核苷酸变异的遗传建模揭示，它在因果上促进了乳腺癌转移。相反，宿主PCSK9的缺失减少了多种乳腺癌模型中的转移性定植。宿主PCSK9通过靶向肿瘤低密度脂蛋白受体相关蛋白1（LRP1）受体，促进了肺部转移的启动事件，并增强了转移性增殖能力，同时抑制了促进转移的基因XAF1和USP18。
抗体介导的PCSK9治疗抑制了多种模型中的乳腺癌转移。在一项大型瑞典早期乳腺癌队列中，rs562556纯合子在15年内出现远处转移性复发的风险为22%，而非纯合子为2%。这些研究结果揭示了一种常见遗传改变在乳腺癌转移中的作用，预测了生存期，并揭示了乳腺癌转移的遗传基础。
附：英文原文
Title: A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor
Author: Wenbin Mei, Schayan Faraj Tabrizi, Christopher Godina, Anthea F. Lovisa, Karolin Isaksson, Helena Jernstrm, Sohail F. Tavazoie
Issue&Volume: 2024-12-09
Abstract: Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 (PCSK9) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival—uncovering a hereditary basis underlying breast cancer metastasis.
DOI: 10.1016/j.cell.2024.11.009
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01326-6