Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China; Breast Cancer Institute, Fujian Medical University, Fuzhou 350001, Fujian Province, China.
Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China; Breast Cancer Institute, Fujian Medical University, Fuzhou 350001, Fujian Province, China.
J Proteomics. 2022 Apr 15;257:104511. doi: 10.1016/j.jprot.2022.104511. Epub 2022 Feb 6.
Invasive micropapillary carcinoma (IMPC) is a rare subtype of breast cancer with an aggressive phenotype and a poor prognosis. The mechanism of tumorigenesis of IMPC in breast remains unknown. Integrative analysis of the proteome and phosphoproteome may shed light on the mechanism of IMPC carcinogenesis. In our study, primary IMPC and paired normal breast tissue were collected from six patients and subjected to label free LC-MS/MS for quantitative proteomic and phosphoproteomic analysis. Kinase-substrate enrichment analysis (KSEA) was conducted to identify hyperactivated/inhibited kinases. Proteomic and phosphoproteomic data was combined to investigate cancer specific activated pathways. A total of 1331 differentially expressed proteins were identified. The proteomic analysis revealed a dysregulation of protein homeostasis in IMPC. Phosphoproteomic profiling identified 856 differentially phosphorylated phosphosites in 655 proteins. KSEA found that cyclin dependent kinases (CDKs) and the p90 ribosomal S6 kinases (RSKs) were highly activated, while protein kinase A (PKA) and protein kinase C (PKC) families were significantly inhibited in IMPC. Finally, cancer-specific activation of mTORC1/S6K2 signaling was also discerned in our integrative analysis. Overall, this study provides a comprehensive landscape of the proteome and phosphoproteome of IMPC, which will contribute to a further understanding of IMPC tumorigenesis and treatment. SIGNIFICANCE: This is the first study to provide the integrative proteomic and phosphoproteomic landscape of IMPC. Our study demonstrated that protein homeostasis dysregulation is one of the most prominent characteristics in IMPC. We also identifying several kinases which might have the potential to be novel targets in clinical practice. Cancer-specific activation of mTORC1/S6K2 signaling was discerned by integrative proteomic and phosphoproteomic analysis. The present study might contribute to a further understanding of IMPC tumorigenesis and treatment.
浸润性微乳头状癌（IMPC）是一种罕见的乳腺癌亚型，具有侵袭性表型和不良预后。IMPC 在乳腺中的肿瘤发生机制尚不清楚。蛋白质组和磷酸化蛋白质组的综合分析可能有助于揭示 IMPC 致癌机制。在我们的研究中，从六名患者中收集了原发性 IMPC 和配对的正常乳腺组织，并进行了无标签 LC-MS/MS 定量蛋白质组学和磷酸化蛋白质组学分析。激酶-底物富集分析（KSEA）用于识别过度激活/抑制的激酶。将蛋白质组学和磷酸化蛋白质组学数据相结合，研究癌症特异性激活途径。共鉴定出 1331 个差异表达蛋白。蛋白质组学分析显示 IMPC 中蛋白质稳态失调。磷酸化蛋白质组学分析鉴定出 655 个蛋白中的 856 个差异磷酸化磷酸化位点。KSEA 发现，在 IMPC 中，周期蛋白依赖性激酶（CDKs）和 p90 核糖体 S6 激酶（RSKs）高度激活，而蛋白激酶 A（PKA）和蛋白激酶 C（PKC）家族明显受到抑制。最后，我们的综合分析还发现了 mTORC1/S6K2 信号的癌症特异性激活。总之，这项研究提供了 IMPC 蛋白质组和磷酸化蛋白质组的综合全景，这将有助于进一步了解 IMPC 的肿瘤发生和治疗。
这是第一项提供 IMPC 综合蛋白质组学和磷酸化蛋白质组学图谱的研究。我们的研究表明，蛋白质稳态失调是 IMPC 最突出的特征之一。我们还鉴定了几种可能具有成为临床实践中新靶点潜力的激酶。通过综合蛋白质组学和磷酸化蛋白质组学分析，发现 mTORC1/S6K2 信号的癌症特异性激活。本研究可能有助于进一步了解 IMPC 的肿瘤发生和治疗。
