School of Medicine, Nankai University, Tianjin, China.
Department of Breast & Thyroid Surgery, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan, China.
Cell Death Dis. 2020 Sep 25;11(9):804. doi: 10.1038/s41419-020-03004-9.
The concept of breast-conserving surgery is a remarkable achievement of breast cancer therapy. Neoadjuvant chemotherapy is being used increasingly to shrink the tumor prior to surgery. Neoadjuvant chemotherapy is reducing the tumor size to make the surgery with less damaging to surrounding tissue and downstage locally inoperable disease to operable. However, non-effective neoadjuvant chemotherapy could increase the risks of delaying surgery, develop unresectable disease and metastatic tumor spread. The biomarkers for predicting the neoadjuvant chemotherapy effect are scarce in breast cancer treatment. In this study, we identified that FZR1 can be a novel biomarker for breast cancer neoadjuvant chemotherapy according to clinical patient cohort evaluation and molecular mechanism investigation. Transcriptomic data analysis indicated that the expression of FZR1 is correlated with the effect of neoadjuvant chemotherapy. Mechanistically, we demonstrate that FZR1 is pivotal to the chemotherapy drugs induced apoptosis and cell cycle arrest. FZR1 is involved in the stability of p53 by impairing the phosphorylation at ser15 site. We demonstrate that the expression of FZR1 detected by quantification of IHC can be an effective predictor of neoadjuvant chemotherapy in animal experiment and clinical patient cohort. To obtain more benefit for breast cancer patient, we propose that the FZR1 IHC score using at the clinical to predict the effect of neoadjuvant chemotherapy.
保乳手术的概念是乳腺癌治疗的一项重大成就。新辅助化疗越来越多地被用于在手术前缩小肿瘤。新辅助化疗可使肿瘤缩小，从而减少手术对周围组织的损伤，并将局部不可手术的疾病降期为可手术。然而，无效的新辅助化疗可能会增加延迟手术、发展为不可切除疾病和转移性肿瘤扩散的风险。在乳腺癌治疗中，预测新辅助化疗效果的生物标志物仍然匮乏。在本研究中，我们通过临床患者队列评估和分子机制研究，发现 FZR1 可以作为乳腺癌新辅助化疗的一个新的生物标志物。转录组数据分析表明，FZR1 的表达与新辅助化疗的效果相关。在机制上，我们证明 FZR1 对化疗药物诱导的细胞凋亡和细胞周期阻滞至关重要。FZR1 通过破坏丝氨酸 15 位的磷酸化来影响 p53 的稳定性。我们通过动物实验和临床患者队列证明，通过免疫组化定量检测到的 FZR1 表达可以作为新辅助化疗的有效预测因子。为了使乳腺癌患者获得更多的益处，我们建议在临床应用 FZR1 的免疫组化评分来预测新辅助化疗的效果。
