Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression.
We demonstrate an integrated approach to the study of a transcriptional regulatory cascade involved in the progression of breast cancer and we identify a protein associated with disease progression. Using chromatin immunoprecipitation and genome tiling arrays, whole genome mapping of transcription factor-binding sites was combined with gene expression profiling to identify genes involved in the proliferative response to estrogen (E2). Using RNA interference, selected ERalpha and c-MYC gene targets were knocked down to identify mediators of E2-stimulated cell proliferation. Tissue microarray screening revealed that high expression of an epigenetic factor, the E2-inducible histone variant H2A.Z, is significantly associated with lymph node metastasis and decreased breast cancer survival. Detection of H2A.Z levels independently increased the prognostic power of biomarkers currently in clinical use. This integrated approach has accelerated the identification of a molecule linked to breast cancer progression, has implications for diagnostic and therapeutic interventions, and can be applied to a wide range of cancers.
Hua
Sujun
S
Joint Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.
Kallen
Caleb B
CB
Dhar
Ruby
R
Baquero
Maria T
MT
Mason
Christopher E
CE
Russell
Beth A
BA
Shah
Parantu K
PK
Liu
Jiang
J
Khramtsov
Andrey
A
Tretiakova
Maria S
MS
Krausz
Thomas N
TN
Olopade
Olufunmilayo I
OI
Rimm
David L
DL
White
Kevin P
KP
D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002843:Chromatin / Q000737:chemistry; D018450:Disease Progression; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D016678:Genome; D006657:Histones / Q000737:chemistry*; D006801:Humans; D008207:Lymphatic Metastasis; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference
D014408:Biomarkers, Tumor; D002843:Chromatin; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006657:Histones; D016271:Proto-Oncogene Proteins c-myc