APOBEC 诱导的突变发生在 50% 已测序的人类肿瘤中，其中 APOBEC3A (A3A) 是乳腺癌细胞突变的主要贡献者。导致乳腺癌中 A3A 激活和突变的机制仍不清楚。在这里，我们描述了影响乳腺癌细胞中基础 A3A mRNA 转录水平的因素。我们发现基础 A3A mRNA 与 A3A 蛋白水平相关，并预测一组乳腺癌细胞系中 APOBEC 特征突变的数量，表明基础转录增加可能是导致乳腺癌突变的一种机制。我们还表明，ERBB2 表达的改变可以驱动 A3A mRNA 水平，这表明富含 Her2 的乳腺癌中 APOBEC 突变特征的富集可能部分是由于 A3A 转录升高所致。原发性乳腺癌转录物的分层聚类确定 A3A mRNA 与在病毒限制和干扰素反应中发挥作用的其他基因共表达。然而，通过抑制剂或 shRNA 减少乳腺癌细胞系中的 STAT 信号传导对 A3A 丰度的影响很小。对原发性肿瘤的单细胞 RNA-seq 分析表明，A3A mRNA 在肿瘤内的浸润性免疫细胞中最高，表明原发性肿瘤中 A3A 与 STAT 信号传导的相关性可能是由于较高的免疫浸润造成的，并不反映 STAT 信号控制A3A 在乳腺癌细胞中的表达。对多个乳腺癌细胞系中 ATAC-seq 数据的分析确定了 APOBEC3A 启动子区域中两个可以促进 A3A 转录的转录因子位点。我们确定 Rel-A 和 Bach1 在这些峰中具有结合位点，可提高基础 A3A 表达。我们的研究结果强调了乳腺癌细胞中 A3A 的一组复杂且可变的转录激活剂。版权所有：© 2024 Dennis 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

APOBEC-induced mutations occur in 50% of sequenced human tumors, with APOBEC3A (A3A) being a major contributor to mutagenesis in breast cancer cells. The mechanisms that cause A3A activation and mutagenesis in breast cancers are still unknown. Here, we describe factors that influence basal A3A mRNA transcript levels in breast cancer cells. We found that basal A3A mRNA correlates with A3A protein levels and predicts the amount of APOBEC signature mutations in a panel of breast cancer cell lines, indicating that increased basal transcription may be one mechanism leading to breast cancer mutagenesis. We also show that alteration of ERBB2 expression can drive A3A mRNA levels, suggesting the enrichment of the APOBEC mutation signature in Her2-enriched breast cancer could in part result from elevated A3A transcription. Hierarchical clustering of transcripts in primary breast cancers determined that A3A mRNA was co-expressed with other genes functioning in viral restriction and interferon responses. However, reduction of STAT signaling via inhibitors or shRNA in breast cancer cell lines had only minor impact on A3A abundance. Analysis of single cell RNA-seq from primary tumors indicated that A3A mRNA was highest in infiltrating immune cells within the tumor, indicating that correlations of A3A with STAT signaling in primary tumors may be result from higher immune infiltrates and are not reflective of STAT signaling controlling A3A expression in breast cancer cells. Analysis of ATAC-seq data in multiple breast cancer cell lines identified two transcription factor sites in the APOBEC3A promoter region that could promote A3A transcription. We determined that Rel-A, and Bach1, which have binding sites in these peaks, elevated basal A3A expression. Our findings highlight a complex and variable set of transcriptional activators for A3A in breast cancer cells.Copyright: © 2024 Dennis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.