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ChIP-Seq analysis to identify direct binding of ZNF165

ABSTRACT: We found that the cancer testis antigen, ZNF165, is required for viability and modulates TGFβ-induced gene expression in mesenchymal, Claudin-Low, TNBC. To begin to define ZNF165's role in TNBC tumorigenesis, we performed ChIP-Seq analysis in the mesenchymal TNBC tumor derived cell line, WHIM12, stably expressing ZNF165-V5. This analysis uncovered 381 peaks associated with 410 genes and included TGFβ target genes, SMURF2 and SMAD, that promote negative TGFβ feedback regulation. Our results provide insight into how ZNF165 globally modulates TGFβ signaling and nominates ZNF165 candidate gene targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65937 | GEO | 2015/11/09

SECONDARY ACCESSION(S): PRJNA275441

REPOSITORIES: GEO

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Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype with few treatment options for chemo-resistant disease. In both preclinical models and patient circulating tumor cells, androgen receptor (AR) expression is increased in anchorage independent TNBC. The AR inhibitor enzalutamide (Enza) leads to reduced TNBC growth in soft agar, invasion, mammosphere formation in vitro, and reduced tumorigenicity and recurrence when combined with chemotherapy in vivo pre-clinical models. Transforming growth factor β (TGFβ) pathway gene signatures are also increased during TNBC anchorage independent survival both in vitro and in vivo in pre-clinical models and CTC from patients during relapse while on chemotherapy. We hypothesized that a positive loop between AR and TGFβ signaling facilitates TNBC anchorage independent survival (anoikis resistance). We previously published that AR protein levels and transcriptional activity increased during anchorage independent conditions and we now find that that multiple components of the TGFβ pathway, including TGFβ1 and 3, as well as pathway activity, as measured by nuclear localization and transcriptional activity of pSmad3, are enhanced in anchorage independent conditions. Indeed, exogenous TGFβ increased AR protein and TGFβ inhibition decreased AR and TNBC viability, particularly under anchorage independent culture conditions. ChIP-Seq experiments revealed AR binding to genomic regions near the TGFB1 and SMAD3. TGFB3 and AR expression were positively correlated in clinical datasets and high levels of co-expression correspond to significantly worse recurrence-free and overall survival in both ER- and basal-like breast cancer. Finally, combining Enza with a TGFβ inhibitor decreased cell survival more than either drug alone, particularly under anchorage independent conditions, where the effect was more than additive. These findings warrant further investigations into whether combined inhibition of AR and TGFβ pathways might decrease metastatic recurrence rates and mortality from TNBC.

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ChIP-Seq analysis to identify direct binding of ZNF165

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