DAB2IP loss in luminal a breast cancer leads to NF-κB–associated aggressive oncogenic phenotypes
Angana Mukherjee, Rasha T. Kakati, Sarah Van Alsten, Tyler Laws, Aaron L. Ebbs, Daniel P. Hollern, Philip M. Spanheimer, Katherine A. Hoadley, Melissa A. Troester, Jeremy M. Simon, Albert S. Baldwin
Angana Mukherjee, Rasha T. Kakati, Sarah Van Alsten, Tyler Laws, Aaron L. Ebbs, Daniel P. Hollern, Philip M. Spanheimer, Katherine A. Hoadley, Melissa A. Troester, Jeremy M. Simon, Albert S. Baldwin
View: Text | PDF
Research Article Oncology

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

Abstract

Despite proven therapy options for estrogen receptor–positive (ER+) breast tumors, a substantial number of patients with ER+ breast cancer exhibit relapse with associated metastasis. Loss of expression of RasGAPs leads to poor outcomes in several cancers, including breast cancer. Mining the The Cancer Genome Atlas (TCGA) breast cancer RNA-Seq dataset revealed that low expression of the RasGAP DAB2IP was associated with a significant decrease in relapse-free survival in patients with Luminal A breast cancer. 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-κB. Integrating cell-based ChIP-Seq with motif analysis and TCGA RNA-Seq data, we identified a set of candidate NF-κB 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.

Authors

Angana Mukherjee, Rasha T. Kakati, Sarah Van Alsten, Tyler Laws, Aaron L. Ebbs, Daniel P. Hollern, Philip M. Spanheimer, Katherine A. Hoadley, Melissa A. Troester, Jeremy M. Simon, Albert S. Baldwin

×

Figure 3

DAB2IP expression decreases with increasing tumor grade and stage in human ER+ and Luminal A–only breast cancer specimens.

Options: View larger image (or click on image) Download as PowerPoint
DAB2IP expression decreases with increasing tumor grade and stage in hum...
(A) Representative images show DAB2IP expression from IHC studies of 116 ER+ breast cancer specimens. Arrows indicate positive cells. Magnification, 10× (top), 20× (bottom). (B and C) Staining intensity of DAB2IP expression per specimen was quantified computationally and plotted by tumor grades and stage, respectively (grade 1 vs. grade 2, *P = 0.0222; grade 1 vs. grade 3, *P = 0.0259; normal vs. grade 2 and normal vs. grade 3, ****P < 0.0001; normal vs. stage II and normal vs. stage III, ****P < 0.0001). (D) DAB2IP expression in TCGA ER+ luminal patients was graphed according to the respective tumor stage (T1–T4) (**P = 0.0035). (E) Representative images show DAB2IP expression of 126 Luminal A breast cancer tissues with arrows indicating positively stained cells. Magnification, 10× (top), 20× (bottom). (F) DAB2IP expression intensity in Luminal A tumors quantified per specimen was graphed by tumor grades (****P < 0.0001). (G) DAB2IP expression in TCGA patients with Luminal A breast cancer was plotted according to the respective tumor stage. Data were analyzed using unpaired Student’s t test, and multiple comparisons were corrected with Dunnett’s test.