尽管雌激素受体（ER）阳性乳腺肿瘤的治疗方案已被证实，但仍有大量 ER 癌症患者出现复发并伴有转移。 RasGAP 表达缺失会导致包括乳腺癌在内的多种癌症的不良预后。挖掘 TCGA 乳腺癌 RNA 测序数据集显示，RasGAP DAB2IP 的低表达与 Luminal A 乳腺癌患者的无复发生存率显着下降相关。免疫染色表明 DAB2IP 丢失发生在 2 级及更高级别的肿瘤中。与此一致的是，DAB2IP 低的 Luminal A 肿瘤中上调的基因与更具侵袭性的肿瘤亚型相同，并且与增殖、转移和 ER 信号传导改变相关。 ER 乳腺癌细胞中 DAB2IP 的低表达与增殖增加、干性表型增强以及转录因子 NF-kB 上游调节因子 IKK 的激活有关。将基于细胞的 ChIP 测序与基序分析和 TCGA RNA-seq 数据相结合，我们鉴定了一组候选 NF-kB 靶基因，这些基因上调且 DAB2IP 丢失，与几种致癌表型（包括 RNA 加工改变）相关。这项研究深入了解了通常侵袭性较低的 Luminal A 乳腺癌固有亚型的一部分中与侵袭性和复发相关的机制。

Despite proven therapy options for estrogen receptor (ER)-positive breast tumors, a substantial number of ER+ cancer patients exhibit relapse with associated metastasis. Loss of expression of RasGAPs leads to poor outcomes in several cancers, including breast cancer. Mining the TCGA breast cancer RNA-sequencing dataset revealed that low expression of the RasGAP DAB2IP was associated with a significant decrease in relapse-free survival in Luminal A breast cancer patients. Immunostaining demonstrated that DAB2IP loss occurred in grade 2 tumors and higher. Consistent with this, genes upregulated in DAB2IP-low Luminal A tumors were shared with more aggressive tumor subtypes and were associated with proliferation, metastasis, and altered ER signaling. Low DAB2IP expression in ER+ breast cancer cells was associated with increased proliferation, enhanced stemness phenotypes, and activation of IKK, the upstream regulator of the transcription factor NF-kB. Integrating cell-based ChIP-sequencing with motif analysis and TCGA RNA-seq data, we identified a set of candidate NF-kB target genes upregulated with loss of DAB2IP linked with several oncogenic phenotypes, including altered RNA processing. This study provides insight into mechanisms associated with aggressiveness and recurrence within a subset of the typically less aggressive Luminal A breast cancer intrinsic subtype.