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DAB2IP Loss in Luminal A Breast Cancer Leads to NF-kB- Associated Aggressive Oncogenic Phenotypes

ABSTRACT: Despite proven therapy options for estrogen receptor (ER)-positive tumors, a significant number of patients with these cancers exhibit relapse with associated metastasis. Studies have shown that the loss of expression of RasGAPs leads to aggressive phenotypes and poor outcomes in several cancers including breast cancer. In our study, mining TCGA gene expression profiles of ER-positive breast tumors, we found that low expression of the RasGAP, DAB2IP is associated with a significant decrease in relapse-free survival in patients with Luminal A breast tumors. Immunostaining found that DAB2IP loss occurs in grade 2 tumors and higher. Consistent with this, genes upregulated in low DAB2IP Luminal A tumors are shared with more aggressive tumor subtypes, and are associated with proliferation, metastasis, and enhanced ER-signaling. In addition, cell-based studies reveal that low DAB2IP expression in ER-positive breast cancer cells is associated with increased proliferation, enhanced stemness phenotypes, and activation of IKK, the upstream regulator of the NF-B signaling pathway. Further, integrating cell-based ChIP-seq with motif analysis and TCGA RNA-seq data, we identify a candidate set of NF-B target genes that are upregulated with loss of DAB2IP and are proposed to regulate several oncogenic phenotypes, including altered RNA processing. This study provides new insight into mechanisms associated with aggressiveness and recurrence within a subset of Luminal A breast cancers that are otherwise typically less aggressive. Gene expression profiling by RNA-sequencing of DAB2IP knockdown and control MCF10A cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227876 | GEO | 2024/12/18

REPOSITORIES: GEO

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Project description:Breast cancer is a heterogeneous disease comprised of at least five major subtypes. Luminal subtype tumors confer a more favourable patient prognosis, which is in part, attributed to the Estrogen Receptor-alpha (ER) positivity and anti-hormone responsiveness of these tumors. Expression of the forkhead box transcription factor, FOXA1, also correlates with the luminal subtype and patient survival, but is present in a subset of ER-negative tumors. Similarly, FOXA1 is consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, basal breast cancer cell lines do not express FOXA1, and loss of FOXA1 in luminal cells increases migration and invasion, characteristics of the basal subtype. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favourable prognosis, we performed cDNA microarray analyses on luminal FOXA1-positive, ER-positive (MCF7, T47D) and FOXA1-positive, ER-negative (MDA-MB-453, SKBR3) cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal-signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Use of Gene Set Enrichment Analyses (GSEA) as a phenotyping tool revealed that FOXA1 silencing resulted in a transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to both luminal and basal genes within luminal breast cancer cells, suggesting that it not only transactivates luminal genes, but also represses basal-associated genes. From these results we conclude that FOXA1 controls plasticity between basal and luminal cells, playing a dominant role in repressing the basal phenotype, and thus tumor aggressiveness, in luminal breast cancer cells. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward a more aggressive cancer. FOXA1 siRNA treated breast cell lines compared directly to nonspecific siRNA treated cell lines using Agilent 4X44 microarrays.

Project description:Breast cancer is a heterogeneous disease comprised of at least five major subtypes. Luminal subtype tumors confer a more favorable patient prognosis, which is in part, attributed to the Estrogen Receptor-α (ER) positivity and anti-hormone responsiveness of these tumors. Expression of the forkhead box transcription factor, FOXA1, also correlates with the luminal subtype and patient survival, but is present in a subset of ER-negative tumors. Similarly, FOXA1 is consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, basal breast cancer cell lines do not express FOXA1, and loss of FOXA1 in luminal cells increases migration and invasion, characteristics of the basal subtype. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favorable prognosis, we performed cDNA microarray analyses on luminal FOXA1-positive, ER-positive (MCF7, T47D) and FOXA1-positive, ER-negative (MDA-MB-453, SKBR3) cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal-signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Use of Gene Set Enrichment Analyses (GSEA) as a phenotyping tool revealed that FOXA1 silencing resulted in a transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to both luminal and basal genes within luminal breast cancer cells, suggesting that it not only transactivates luminal genes, but also represses basal-associated genes. From these results we conclude that FOXA1 controls plasticity between basal and luminal cells, playing a dominant role in repressing the basal phenotype, and thus tumor aggressiveness, in luminal breast cancer cells. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward a more aggressive cancer.

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DAB2IP Loss in Luminal A Breast Cancer Leads to NF-kB- Associated Aggressive Oncogenic Phenotypes

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