Song Qi, Wang Yixuan, Liu Sen
Cooperative Innovation Center of Industrial Fermentation (Ministry of Education and Hubei Province) Key Laboratory of Fermentation Engineering (Ministry of Education) Wuhan Hubei China.
Hubei Key Laboratory of Industrial Microbiology, National "111" Center for Cellular Regulation and Molecular Pharmaceutics Hubei University of Technology Wuhan Hubei China.
Cancer Innov. 2024 Dec 2;4(1):e138. doi: 10.1002/cai2.138. eCollection 2025 Feb.
Polyamines play important roles in cell growth and proliferation. Polyamine metabolism genes are dysregulated in various tumors. Some polyamine metabolism genes are regulated by transcription factors. However, the transcription factors that regulate polyamine metabolism genes have not been completely identified. Additionally, whether any of the transcriptional regulations depend on tumor heterogeneity and the tumor microenvironment has not been investigated.
We used bulk RNA-seq data to identify dysregulated polyamine metabolism genes and their transcription factors across breast cancer subtypes. Genes highly correlated with polyamine changes were obtained, and their subtype-specific expressions were checked in tumor microenvironment cells using single-cell RNA (scRNA)-seq data. Gene Ontology enrichment analysis was used to explore their molecular functions and biological processes, and survival analysis was used to examine the impact of these genes on therapeutic outcome.
We first analyzed the dysregulation of polyamine synthesis, catabolism, and transport in four breast cancer subtypes. Genes such as and were dysregulated across all subtypes, while , , and other genes were dysregulated in the more lethal subtypes. Among the dysregulated genes of polyamine metabolism, we focused on three genes (, , and ) and identified their transcription factors (SPI1 and IRF1 correspond to , and IRF3 corresponds to and ). With scRNA-seq data, we verified that these three transcription factors also regulated these three polyamine metabolism genes in the tumor microenvironment. Both bulk RNA-seq and scRNA-seq data indicated that these genes were specifically upregulated in high-risk breast cancer subtypes, such as the basal-like type. High expression of these genes corresponded to worse outcomes in the basal-like subtype under chemotherapy and radiation treatment.
Our work identified three subtype-specific transcription factors that regulate three polyamine metabolism genes in high-risk breast cancer subtypes and the tumor microenvironment. Our results deepen the understanding of the role of polyamine metabolism in breast cancer and may help the clinical therapy of advanced breast cancer subtypes.
多胺在细胞生长和增殖中发挥重要作用。多胺代谢基因在各种肿瘤中失调。一些多胺代谢基因受转录因子调控。然而，调控多胺代谢基因的转录因子尚未完全确定。此外，尚未研究任何转录调控是否依赖于肿瘤异质性和肿瘤微环境。
我们使用批量RNA测序数据来识别乳腺癌各亚型中失调的多胺代谢基因及其转录因子。获得与多胺变化高度相关的基因，并使用单细胞RNA（scRNA）测序数据在肿瘤微环境细胞中检查它们的亚型特异性表达。基因本体富集分析用于探索它们的分子功能和生物学过程，生存分析用于检查这些基因对治疗结果的影响。
我们首先分析了四种乳腺癌亚型中多胺合成、分解代谢和转运的失调情况。诸如[具体基因1]和[具体基因2]等基因在所有亚型中均失调，而[具体基因3]、[具体基因4]和其他基因在更具致死性的亚型中失调。在多胺代谢失调的基因中，我们聚焦于三个基因（[具体基因5]、[具体基因6]和[具体基因7]），并确定了它们的转录因子（SPI1和IRF1对应于[具体基因5]，IRF3对应于[具体基因6]和[具体基因7]）。利用scRNA测序数据，我们验证了这三种转录因子在肿瘤微环境中也调控这三个多胺代谢基因。批量RNA测序和scRNA测序数据均表明，这些基因在高危乳腺癌亚型（如基底样型）中特异性上调。这些基因的高表达对应于基底样亚型在化疗和放疗下更差的预后。
我们的工作确定了三种亚型特异性转录因子，它们在高危乳腺癌亚型和肿瘤微环境中调控三个多胺代谢基因。我们的结果加深了对多胺代谢在乳腺癌中作用的理解，并可能有助于晚期乳腺癌亚型的临床治疗。
