In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 22_Supplement_1 ( 2015-11-15), p. A1-14-A1-14
Abstract:
Estrogen receptor (ER) positive luminal breast cancer represents approx 70% of all newly diagnosed breast cancers. ER is known to drive breast cancer development and progression, and targeting ER has been one of the most successful targeted therapies in oncology. Given the paucity of functional DNA sequence variants (DSVs) within the ER in primary breast tumors, we asked whether DSVs in ER binding sites could contribute to altered hormone response through changes in ER recruitment to DNA. We developed a pipeline to extract DSVs in ER binding sites, and to assess their impact on ER binding in a genome-wide manner, using ChIP-seq data from hormone responsive breast cancer cells. We utilized MACS for peak calling and GATK for calling DSVs including SNVs and short indels. Using 22,143 ER binding sites which overlapped in at least six data sets, we detected 1,409,406 DSVs from 441,855,039 reads. Position weight matrix (PWM) was used to scan the genome for potential ERE motifs, and identified 126 potential DSVs which were predicted to change ER binding. Of those, 29 DSV-containing EREs were in proximity or within estrogen regulated genes. Intriguingly, the top hit was a previously reported SNP within intron 2 of the IGF1R gene (rs62022087), which our data predicted to increase the affinity for ER binding. The ERE lies in a regulatory region characterized by active histone marks such as H3K29ac and H3k4Me1, and recruitment of a number of transcription factors including c-myc, FoxA1, GATA-1, and finally DNase I hypersensitive sites. Further analysis of published ChIP-seq studies on 6 ER+ cell lines and 15 primary tumors revealed that the presence of rs62022087 was associated with the enrichment of reads over the ER binding site, suggesting that the DSV indeed increases binding affinity of ER. Our further in-vitro functional studies confirmed that ER is more preferentially binding to mutant allele vs wild-type allele. In summary, we have shown that our pipeline is capable of predicting potential regulatory DSVs in ER binding sites. Studies are ongoing to understand functional and clinical relevance of rs62022087, especially with respect to crosstalk between estrogen and IGF1 signaling. Citation Format: Amir Bahreini, Amir Bahreini, Lucas Santanas, Peilu Wang, Panayiotis V. Benos, Adrian V. Lee, Adrian V. Lee, Steffi Oesterreich, Steff Oesterreich. Discovery of a functional SNP in an estrogen receptor binding site in the IGF1R gene. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-14.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.TRANSCAGEN-A1-14
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Bookmarklink
