Hallmarks of aromatase inhibitor drug resistance revealed by epigenetic profiling in breast cancer.
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 α (ERα), along with the epigenetic modifications H3K4me3 and H3K27me3, that are responsible for determining gene transcription (n = 12). Differential binding patterns of ERα, H3K4me3, and H3K27me3 were enriched between patients with good or poor outcomes after aromatase inhibition. ERα and H3K27me3 patterns were validated in an additional independent set of breast cancer cases (n = 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 ERα 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.
Authors' Affiliations: Department of Medical Oncology, Erasmus University Medical Center, Cancer Institute, Rotterdam; Departments of Molecular Carcinogenesis and Molecular Pathology, Central Genomic Facility, the Netherlands Cancer Institute; Agendia NV, Amsterdam, the Netherlands; and Translational Cancer Research Unit, Laboratory of Pathology, Antwerp University/Oncology Centre, GZA Hospitals St-Augustinus, Antwerp, Belgium.
Maurice P H M
MP
Jansen
Theo
T
Knijnenburg
Esther A
EA
Reijm
Iris
I
Simon
Ron
R
Kerkhoven
Marjolein
M
Droog
Arno
A
Velds
Steven
S
van Laere
Luc
L
Dirix
Xanthippi
X
Alexi
John A
JA
Foekens
Lodewyk
L
Wessels
Sabine C
SC
Linn
Els M J J
EM
Berns
Wilbert
W
Zwart
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D015331:Cohort Studies; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D059467:Transcriptome
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D006657:Histones; D011495:Histone-Lysine N-Methyltransferase