PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
AR chromatin binding is reprogrammed in the absence of FOXA1 in ER- breast cancers
Iza Denis 1 , Luke A Selth 1 , Jessica LL Robinson 2, , Hisham Mohammed 2, , Thomas Carroll 2, , Gordon D Brown 2, , David E Neal 2, , Jason S Carroll 2, , Wayne D Tilley 1 & Theresa E Hickey 1
1Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, AHMS, University of Adelaide, Adelaide, SA 5005, Australia; 2Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK; 3Department of Oncology, University of Cambridge, Cambridge, CB2 0XZ, UK.
Introduction: 75% of breast cancers (BCa) are driven by the estrogen receptor α (ER+). Tumours lacking ER (ER-) are more aggressive and have the poorest prognosis. The androgen receptor (AR) is also widely expressed in BCa (90% of primary tumours). FOXA1 is a pioneer factor required for oncogenic AR signalling in PCa but its role in AR signaling in ER-BCa is not clear. We previously showed that cell growth is increased when FOXA1 is overexpressed in AR-driven PCa and BCa cell lines, suggesting that FOXA1 enhances growth. To further address FOXA1’s role in ER- BCa, we examined the consequence of FOXA1 loss on AR-chromatin interactions (cistrome) in a well characterized model of AR driven ER-BCa.
Hypothesis: AR cistrome is reprogrammed in the absence of FOXA1 in ER- BCa.
Methods: Genome-wide chromatin binding profiles for AR and specific AR interactors were performed using ChIP-seq in the ER-AR+ MDA-MB-453 BCa cell line. The AR protein interactome was interrogated using SILAC-RIME proteomic technique.
Results: Depletion of FOXA1 inhibited MDA-MB-453 cell proliferation, suggesting a requirement for FOXA1 to sustain cell growth. AR recruitment was increased at a large number of sites (73%) in the absence of FOXA1, suggesting that AR chromatin binding is reprogrammed when FOXA1 is missing. Proteomic analysis in the absence of FOXA1 revealed an increased interaction of AR with several proteins, including TFAP2A. Motif analysis indicated that the gained AR binding sites were enriched for TFAP2A binding motifs; co-IP analyses confirmed the interaction between AR and TFAP2A. Co-localisation of core TFAP2A, AR and FOXA1 binding events (20% overlap) was identified.
Conclusion: In the absence of FOXA1, AR cistrome is reprogrammed in ER-AR+ MDA-MB-453 cells. The gained genomic AR binding sites appear to be dependent on a novel factor, TFAP2A, which could to be critical for AR signaling.
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Oncology Abstracts
ISSN 2631-4657 (online)
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