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Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression.

Hua S, Kallen CB, Dhar R, Baquero MT, Mason CE, Russell BA, Shah PK, Liu J, Khramtsov A, Tretiakova MS, Krausz TN, Olopade OI, Rimm DL, White KP - Mol. Syst. Biol. (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Joint Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.

ABSTRACT
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.

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Time course of E2-responsive genes in MCF7 cells. Time course of significantly up- and downregulated genes in MCF7 cells after stimulation with 10 nM 17β-estradiol (E2) is shown. Overlapping gene counts for three time points (4, 12, and 24 h) are shown for upregulated (A) and downregulated (B) genes (all P<0.01).
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f4: Time course of E2-responsive genes in MCF7 cells. Time course of significantly up- and downregulated genes in MCF7 cells after stimulation with 10 nM 17β-estradiol (E2) is shown. Overlapping gene counts for three time points (4, 12, and 24 h) are shown for upregulated (A) and downregulated (B) genes (all P<0.01).

Mentions: We measured gene expression changes in MCF7 cells after 4, 12, and 24 h of E2 treatment (Figure 4 and Supplementary Table 3). Gene expression profiling was combined with direct ERα-binding site localization to reveal that 5.1% of ERα-binding sites were within 10 kb of the TSS of any E2-responsive gene (Supplementary Table 4), consistent with the observation that ERα often binds far from target TSSs (Figures 1A and 3B). Nevertheless, these results revealed significant enrichment of receptor binding near regulated genes when compared to expectations generated by a random distribution model (P<5.4e−6). When we considered ERα-binding sites within 200 kb of any TSS, we found that 39% were in the vicinity of an E2-responsive gene (P<4.1e−12). The 61% of ERα-binding sites that were greater than 200 kb from any E2-responsive TSS may be regulating genes from extreme distances, may be regulating genes that are not currently annotated or may be inactive in MCF7 cells.


Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression.

Hua S, Kallen CB, Dhar R, Baquero MT, Mason CE, Russell BA, Shah PK, Liu J, Khramtsov A, Tretiakova MS, Krausz TN, Olopade OI, Rimm DL, White KP - Mol. Syst. Biol. (2008)

Time course of E2-responsive genes in MCF7 cells. Time course of significantly up- and downregulated genes in MCF7 cells after stimulation with 10 nM 17β-estradiol (E2) is shown. Overlapping gene counts for three time points (4, 12, and 24 h) are shown for upregulated (A) and downregulated (B) genes (all P<0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2394496&req=5

f4: Time course of E2-responsive genes in MCF7 cells. Time course of significantly up- and downregulated genes in MCF7 cells after stimulation with 10 nM 17β-estradiol (E2) is shown. Overlapping gene counts for three time points (4, 12, and 24 h) are shown for upregulated (A) and downregulated (B) genes (all P<0.01).
Mentions: We measured gene expression changes in MCF7 cells after 4, 12, and 24 h of E2 treatment (Figure 4 and Supplementary Table 3). Gene expression profiling was combined with direct ERα-binding site localization to reveal that 5.1% of ERα-binding sites were within 10 kb of the TSS of any E2-responsive gene (Supplementary Table 4), consistent with the observation that ERα often binds far from target TSSs (Figures 1A and 3B). Nevertheless, these results revealed significant enrichment of receptor binding near regulated genes when compared to expectations generated by a random distribution model (P<5.4e−6). When we considered ERα-binding sites within 200 kb of any TSS, we found that 39% were in the vicinity of an E2-responsive gene (P<4.1e−12). The 61% of ERα-binding sites that were greater than 200 kb from any E2-responsive TSS may be regulating genes from extreme distances, may be regulating genes that are not currently annotated or may be inactive in MCF7 cells.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Joint Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus