Hatoum Diana, Yagoub Daniel, Ahadi Alireza, Nassif Najah T, McGowan Eileen M
School of Life Sciences, Faculty of Science, Faculty of Engineering and IT, University of Technology Sydney, Sydney, New South Wales, Australia.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia.
PLoS One. 2017 Jan 9;12(1):e0169925. doi: 10.1371/journal.pone.0169925. eCollection 2017.
The annexin family and S100A associated proteins are important regulators of diverse calcium-dependent cellular processes including cell division, growth regulation and apoptosis. Dysfunction of individual annexin and S100A proteins is associated with cancer progression, metastasis and cancer drug resistance. This manuscript describes the novel finding of differential regulation of the annexin and S100A family of proteins by activation of p53 in breast cancer cells. Additionally, the observed differential regulation is found to be beneficial to the survival of breast cancer cells and to influence treatment efficacy. We have used unbiased, quantitative proteomics to determine the proteomic changes occurring post p14ARF-p53 activation in estrogen receptor (ER) breast cancer cells. In this report we identified differential regulation of the annexin/S100A family, through unique peptide recognition at the N-terminal regions, demonstrating p14ARF-p53 is a central orchestrator of the annexin/S100A family of calcium regulators in favor of pro-survival functions in the breast cancer cell. This regulation was found to be cell-type specific. Retrospective human breast cancer studies have demonstrated that tumors with functional wild type p53 (p53wt) respond poorly to some chemotherapy agents compared to tumors with a non-functional p53. Given that modulation of calcium signaling has been demonstrated to change sensitivity of chemotherapeutic agents to apoptotic signals, in principle, we explored the paradigm of how p53 modulation of calcium regulators in ER+ breast cancer patients impacts and influences therapeutic outcomes.
膜联蛋白家族和S100A相关蛋白是多种钙依赖性细胞过程的重要调节因子，这些过程包括细胞分裂、生长调节和细胞凋亡。单个膜联蛋白和S100A蛋白的功能障碍与癌症进展、转移和癌症耐药性相关。本手稿描述了在乳腺癌细胞中通过激活p53对膜联蛋白和S100A蛋白家族进行差异调节这一全新发现。此外，观察到的这种差异调节有利于乳腺癌细胞的存活并影响治疗效果。我们使用了无偏差定量蛋白质组学来确定雌激素受体（ER）阳性乳腺癌细胞中p14ARF-p53激活后发生的蛋白质组变化。在本报告中，我们通过在N端区域的独特肽段识别鉴定了膜联蛋白/S100A家族的差异调节，证明p14ARF-p53是膜联蛋白/S100A钙调节蛋白家族的核心协调因子，有利于乳腺癌细胞的促存活功能。发现这种调节具有细胞类型特异性。回顾性人类乳腺癌研究表明，与具有无功能p53的肿瘤相比，具有功能性野生型p53（p53wt）的肿瘤对某些化疗药物反应较差。鉴于已证明钙信号的调节可改变化疗药物对凋亡信号的敏感性，原则上，我们探讨了ER阳性乳腺癌患者中p53对钙调节蛋白的调节如何影响治疗结果这一模式。
