Hallmarks of Aromatase Inhibitor Drug Resistance Revealed by Epigenetic Profiling in Breast Cancer

Abstract

Aromatase inhibitors are the major first-line treatment of estrogen receptor-positive breast cancer, but resistance to treatment is common. To date, no biomarkers have been validated clinically to guide subsequent therapy in these patients. In this study, we mapped the genome-wide chromatin-binding profiles of estrogen receptor a (ERa), along with the epigenetic modifications H3K4me3 and H3K27me3, that are responsible for determining gene transcription (n ¼ 12). Differential binding patterns of ERa, H3K4me3, and H3K27me3 were enriched between patients with good or poor outcomes after aromatase inhibition. ERa and H3K27me3 patterns were validated in an additional independent set of breast cancer cases (n ¼ 10). We coupled these patterns to array-based proximal gene expression and progression-free survival data derived from a further independent cohort of 72 aromatase inhibitor-treated patients. Through this approach, we determined that the ERa and H3K27me3 profiles predicted the treatment outcomes for first-line aromatase inhibitors. In contrast, the H3K4me3 pattern identified was not similarly informative. The classification potential of these genes was only partially preserved in a cohort of 101 patients who received first-line tamoxifen treatment, suggesting some treatment selectivity in patient classification. Cancer Res; 73(22); 6632-41. Ó2013 AACR.

Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas

“…1B), but still quantifiably detected and enriched over background ( Fig. 1C and D (25,30), endometrial ERa is rarely found at promoters and mainly binds distal intergenic regions and introns (Fig. 1E).…”

“…Primer sequences used for ChIP-qPCR are listed in Supplementary Table S3. All Ishikawa ChIP-seq and RNA-seq datasets were generated by the ENCODE consortium, and Supplementary Table S4 shows all accession numbers of the used datasets that also includes breast cancer ERa ChIP-seq data from Jansen and colleagues (25). Patient characteristics of breast cancer tumors can be found in Supplementary Table S5.…”

SRC3 Phosphorylation at Serine 543 Is a Positive Independent Prognostic Factor in ER-Positive Breast Cancer

“…After 10 minutes of fixation, 100 mmol/L Glycine as added, after which cells were washed in PBS in presence of protease inhibitor (Roche Diagnostics 11836145001) and phosphatase inhibitors (Roche Diagnostics: 04906837001) at concentrations recommended by the supplier. Tissue was homogenized, and nuclei were isolated, washed, and sonicated using a Diagenode Bioruptor as described before (21,22). After sonication, the lysate was cleared by centrifugation.…”

A review of estrogen receptor/androgen receptor genomics in male breast cancer

“…As endocrine therapy resistance is clinically identified at the level of recurrent disease, a clear clinical need exists to identify markers for endocrine resistance at an early stage, so that patients with a predicted resistance can be treated with an alternative treatment instead. ERα and AR both have thousands of known DNA-binding sites in breast and prostate cancer, respectively (Carroll et al 2006, Chng et al 2012, Jansen et al 2013, Zwart et al 2013, Stelloo et al 2015, Severson et al 2016. Differential binding at these sites can be indicative of outcome in both breast and prostate cancer.…”

“…In FBC, genome-wide ERα/DNA binding profiles determined by chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) have been found to be dynamic upon tamoxifen exposure (Severson et al 2016) and more importantly are associated with differential outcome (Ross-Innes et al 2012, Jansen et al 2013. H3K27ac signal, a histone modification indicative of active enhancers at ERα-binding regions, is similar between male and female tissues suggesting the inherent transcriptional programming between genders is comparable (ENCODE Project Consortium 2012).…”