Aziz Diar, Lee Christine, Chin Venessa, Fernandez Kristine J, Phan Zoe, Waring Paul, Caldon C Elizabeth
Centre for Translational Pathology, Department of Pathology, University of Melbourne, Parkville, VIC, Australia.
Department of Surgery, University of Melbourne, Parkville, VIC, Australia.
J Pathol Clin Res. 2022 Jul;8(4):355-370. doi: 10.1002/cjp2.269. Epub 2022 Apr 6.
Basal-like breast cancer (BLBC) has a greater overlap in molecular features with high-grade serous ovarian cancer (HGSOC) than with other breast cancer subtypes. Similarities include BRCA1 mutation, high frequency of TP53 mutation, and amplification of CCNE1 (encoding the cyclin E1 protein) in 6-34% of cases, and these features can be used to group patients for targeted therapies in clinical trials. In HGSOC, we previously reported two subsets with high levels of cyclin E1: those in which CCNE1 is amplified, have intact homologous recombination (HR), and very poor prognosis; and a CCNE1 non-amplified subset, with more prevalent HR defects. Here, we investigate whether similar subsets are identifiable in BLBC that may allow alignment of patient grouping in clinical trials of agents targeting cyclin E1 overexpression. We examined cyclin E1 protein and CCNE1 amplification in a cohort of 76 BLBCs and validated the findings in additional breast cancer datasets. Compared to HGSOC, CCNE1 amplified BLBC had a lower level of amplification (3.5 versus 5.2 copies) and lower relative cyclin E1 protein, a lack of correlation of amplification with expression, and no association with polyploidy. BLBC with elevated cyclin E1 protein also had prevalent HR defects, and high-level expression of the cyclin E1 deubiquitinase ubiquitin-specific protease 28 (USP28). Using a meta-analysis across multiple studies, we determined that cyclin E1 protein overexpression but not amplification is prognostic in BLBC, while both cyclin E1 overexpression and amplification are prognostic in HGSOC. Overall CCNE1 gene amplification is not equivalent between BLBC and HGSOC. However, high cyclin E1 protein expression can co-occur with HR defects in both BLBC and HGSOC, and is associated with poor prognosis in BLBC.
基底样乳腺癌（BLBC）在分子特征上与高级别浆液性卵巢癌（HGSOC）的重叠程度高于其他乳腺癌亚型。相似之处包括BRCA1突变、TP53突变的高频率以及6%-34%的病例中CCNE1（编码细胞周期蛋白E1蛋白）的扩增，这些特征可用于在临床试验中对患者进行分组以进行靶向治疗。在HGSOC中，我们之前报道了两个细胞周期蛋白E1水平较高的亚组：其中CCNE1扩增、同源重组（HR）完整且预后极差的亚组；以及CCNE1未扩增的亚组，其HR缺陷更为普遍。在此，我们研究在BLBC中是否可识别出类似的亚组，这可能有助于在针对细胞周期蛋白E1过表达的药物临床试验中使患者分组保持一致。我们检测了76例BLBC样本中的细胞周期蛋白E1蛋白和CCNE1扩增情况，并在其他乳腺癌数据集中验证了结果。与HGSOC相比，CCNE1扩增的BLBC扩增水平较低（3.5个拷贝对5.2个拷贝）且细胞周期蛋白E1相对蛋白水平较低，扩增与表达缺乏相关性，且与多倍体无关。细胞周期蛋白E1蛋白升高的BLBC也存在普遍的HR缺陷，以及细胞周期蛋白E1去泛素化酶泛素特异性蛋白酶28（USP28）的高水平表达。通过对多项研究的荟萃分析，我们确定细胞周期蛋白E1蛋白过表达而非扩增在BLBC中具有预后意义，而细胞周期蛋白E1过表达和扩增在HGSOC中均具有预后意义。总体而言，CCNE1基因扩增在BLBC和HGSOC中并不等同。然而，高细胞周期蛋白E1蛋白表达在BLBC和HGSOC中均可与HR缺陷同时出现，且与BLBC的不良预后相关。
