DAB2IP loss in luminal a breast cancer leads to NF-κB-associated aggressive oncogenic phenotypes

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Estrogen receptor-positive (ER+) breast cancer can recur and metastasize despite effective therapies.
• Loss of Ras GTPase-activating protein (RasGAP) expression is linked to poor outcomes in various cancers, including breast cancer.

Purpose of the Study:

• To investigate the role of RasGAP DAB2IP expression in ER+ breast cancer, particularly in Luminal A subtype recurrence.
• To identify molecular mechanisms underlying tumor aggressiveness and metastasis associated with DAB2IP loss.

Main Methods:

• Analysis of The Cancer Genome Atlas (TCGA) breast cancer RNA-Seq dataset.
• Immunohistochemical staining for DAB2IP expression in tumor samples.
• Cell-based experiments assessing proliferation, stemness, and signaling pathways (IKK/NF-κB).
• Chromatin immunoprecipitation sequencing (ChIP-Seq) integrated with motif analysis.

Main Results:

• Low DAB2IP expression in Luminal A breast cancer correlates with decreased relapse-free survival.
• DAB2IP loss is observed in higher-grade tumors (grade 2+).
• Upregulated genes in DAB2IP-low tumors are associated with proliferation, metastasis, and altered ER signaling.
• Reduced DAB2IP expression enhances cell proliferation, stemness, and activates the IKK/NF-κB pathway.
• NF-κB target genes linked to oncogenic phenotypes, including altered RNA processing, are identified.

Conclusions:

• Loss of DAB2IP contributes to aggressiveness and recurrence in a subset of ER+ breast cancers.
• The study elucidates a mechanism involving DAB2IP, NF-κB signaling, and oncogenic phenotypes in breast cancer progression.
• Findings provide insights into therapeutic strategies targeting DAB2IP-deficient ER+ breast tumors.