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Prognostic features of signal transducer and activator of transcription 3 in an ER(+) breast cancer model system.

Liu LY, Chang LY, Kuo WH, Hwa HL, Lin YS, Jeng MH, Roth DA, Chang KJ, Hsieh FJ - Cancer Inform (2014)

Bottom Line: These data predict malignant events, treatment responses and a novel enhancer of tamoxifen resistance.Taken together, we identify a poor prognosis relevant gene set within the STAT3 network and a robust one in a subset of patients.VEGFA, ABL1, LYN, IGF2R and STAT3 are suggested therapeutic targets for further study based upon the degree of differential expression in our model.

View Article: PubMed Central - PubMed

Affiliation: Department of Agronomy, Biometry Division, National Taiwan University, Taipei, Taiwan.

ABSTRACT
The aberrantly expressed signal transducer and activator of transcription 3 (STAT3) predicts poor prognosis, primarily in estrogen receptor positive (ER(+)) breast cancers. Activated STAT3 is overexpressed in luminal A subtype cells. The mechanisms contributing to the prognosis and/or subtype relevant features of STAT3 in ER(+) breast cancers are through multiple interacting regulatory pathways, including STAT3-MYC, STAT3-ERα, and STAT3-MYC-ERα interactions, as well as the direct action of activated STAT3. These data predict malignant events, treatment responses and a novel enhancer of tamoxifen resistance. The inferred crosstalk between ERα and STAT3 in regulating their shared target gene-METAP2 is partially validated in the luminal B breast cancer cell line-MCF7. Taken together, we identify a poor prognosis relevant gene set within the STAT3 network and a robust one in a subset of patients. VEGFA, ABL1, LYN, IGF2R and STAT3 are suggested therapeutic targets for further study based upon the degree of differential expression in our model.

No MeSH data available.


Related in: MedlinePlus

In vitro validation of an ERα target gene—METAP2 (p67).The upper left panel shows the results of western blot analysis on protein expression levels of METAP2 (p67) in MCF-7 cell model (A).Western blot analysis for METAP2 encoded protein indicates it to be regulated by ERα. We found increased p67 protein in MCF-7 with E2 treatment as compared to that with fulvestrant (ICI 182, 780 or ICI) treatment, (ICI + E2) treatment and control. MCF-7 cells were deprived of estrogen for 2 days and treated with 10−9 M E2 (labeled as + E2), 10−7 M ICI183,780 (labeled as + ICI183,780), or a combination of both (ICI + E2) for 48 hours. Total lysate (60 μg/lane) from MCF-7 cells was resolved in 7.5% SDS-PAGE and immunoblotted with anti-rat p67. β-actin was as the loading control. The lower blot was probed with anti-β-actin. The upper right panel shows that a diagram of the network prediction for interaction between ERα and STAT3 results in a switch in expression mode of their potential target gene-METAP2, which is predicted to be subtype relevant in ER(+) IDCs (B).Moreover, METAP2 is predicted to be shared target genes due to the combinatorial interaction of 2 given transcription factors (see the overlapping network of MYCnSTAT3 and ESR1nSTAT3 in Table S2.4 of Suppl. 2) but it is neither in the overlapping network of ESR1 and STAT3 nor in that of MYC and STAT3 (Table S2.6 in Suppl. 2). Based on the network analysis results, the proposed interplay between promoter use pathways of ESR1 nSTAT3 and MYCnSTAT3 in luminal A and B in regulating METAP2 is proposed (B).The lower left panel demonstrates that DNA sequence of promoter region for rat METAP2 (p67) (GenBank: U37710) includes 5 3′ ERE half-sites45 and a 5′Am2Tp2 variant site46 (C). This indicates rat METAP2 to be a target gene of ERα due to the half-ERE sites to be the candidate binding sites of ERα.The lower right panel demonstrates that DNA sequence of promoter region for mouse METAP2 (p67) includes two 5′ ERE half-sites and two 3′ ERE half-sites (D). This indicates mouse METAP2 to be a target gene of ERα due to the half-ERE sites to be the candidate binding sites of ERα.
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f5-cin-13-2014-021: In vitro validation of an ERα target gene—METAP2 (p67).The upper left panel shows the results of western blot analysis on protein expression levels of METAP2 (p67) in MCF-7 cell model (A).Western blot analysis for METAP2 encoded protein indicates it to be regulated by ERα. We found increased p67 protein in MCF-7 with E2 treatment as compared to that with fulvestrant (ICI 182, 780 or ICI) treatment, (ICI + E2) treatment and control. MCF-7 cells were deprived of estrogen for 2 days and treated with 10−9 M E2 (labeled as + E2), 10−7 M ICI183,780 (labeled as + ICI183,780), or a combination of both (ICI + E2) for 48 hours. Total lysate (60 μg/lane) from MCF-7 cells was resolved in 7.5% SDS-PAGE and immunoblotted with anti-rat p67. β-actin was as the loading control. The lower blot was probed with anti-β-actin. The upper right panel shows that a diagram of the network prediction for interaction between ERα and STAT3 results in a switch in expression mode of their potential target gene-METAP2, which is predicted to be subtype relevant in ER(+) IDCs (B).Moreover, METAP2 is predicted to be shared target genes due to the combinatorial interaction of 2 given transcription factors (see the overlapping network of MYCnSTAT3 and ESR1nSTAT3 in Table S2.4 of Suppl. 2) but it is neither in the overlapping network of ESR1 and STAT3 nor in that of MYC and STAT3 (Table S2.6 in Suppl. 2). Based on the network analysis results, the proposed interplay between promoter use pathways of ESR1 nSTAT3 and MYCnSTAT3 in luminal A and B in regulating METAP2 is proposed (B).The lower left panel demonstrates that DNA sequence of promoter region for rat METAP2 (p67) (GenBank: U37710) includes 5 3′ ERE half-sites45 and a 5′Am2Tp2 variant site46 (C). This indicates rat METAP2 to be a target gene of ERα due to the half-ERE sites to be the candidate binding sites of ERα.The lower right panel demonstrates that DNA sequence of promoter region for mouse METAP2 (p67) includes two 5′ ERE half-sites and two 3′ ERE half-sites (D). This indicates mouse METAP2 to be a target gene of ERα due to the half-ERE sites to be the candidate binding sites of ERα.

Mentions: The STAT3 network is predicted to regulate only a subset of genes in the Warburg effect. Relatively low expression levels of LDHB and LDHA indicate that part of the Warburg effect may be suppressed in ER(+)BCs (Figs. 3C and 4B). In addition, MYC and STAT3 differentially regulate the expression of subunits for succinate dehydrogenase (SDH) that may alter the enzyme activities of SDH. However, the expression pattern of PC and GLS are conserved between ER(+) and ER(−) breast cancers (Figs. 5D9 and 3C). They do not follow the same regulatory route within the STAT3 transcriptional regulatory network. Based upon these results, the physiological role for high levels of LDHB, PC, SDHD and a transcript variant of MYC in non-tumor components could be of interest for future study.


Prognostic features of signal transducer and activator of transcription 3 in an ER(+) breast cancer model system.

Liu LY, Chang LY, Kuo WH, Hwa HL, Lin YS, Jeng MH, Roth DA, Chang KJ, Hsieh FJ - Cancer Inform (2014)

In vitro validation of an ERα target gene—METAP2 (p67).The upper left panel shows the results of western blot analysis on protein expression levels of METAP2 (p67) in MCF-7 cell model (A).Western blot analysis for METAP2 encoded protein indicates it to be regulated by ERα. We found increased p67 protein in MCF-7 with E2 treatment as compared to that with fulvestrant (ICI 182, 780 or ICI) treatment, (ICI + E2) treatment and control. MCF-7 cells were deprived of estrogen for 2 days and treated with 10−9 M E2 (labeled as + E2), 10−7 M ICI183,780 (labeled as + ICI183,780), or a combination of both (ICI + E2) for 48 hours. Total lysate (60 μg/lane) from MCF-7 cells was resolved in 7.5% SDS-PAGE and immunoblotted with anti-rat p67. β-actin was as the loading control. The lower blot was probed with anti-β-actin. The upper right panel shows that a diagram of the network prediction for interaction between ERα and STAT3 results in a switch in expression mode of their potential target gene-METAP2, which is predicted to be subtype relevant in ER(+) IDCs (B).Moreover, METAP2 is predicted to be shared target genes due to the combinatorial interaction of 2 given transcription factors (see the overlapping network of MYCnSTAT3 and ESR1nSTAT3 in Table S2.4 of Suppl. 2) but it is neither in the overlapping network of ESR1 and STAT3 nor in that of MYC and STAT3 (Table S2.6 in Suppl. 2). Based on the network analysis results, the proposed interplay between promoter use pathways of ESR1 nSTAT3 and MYCnSTAT3 in luminal A and B in regulating METAP2 is proposed (B).The lower left panel demonstrates that DNA sequence of promoter region for rat METAP2 (p67) (GenBank: U37710) includes 5 3′ ERE half-sites45 and a 5′Am2Tp2 variant site46 (C). This indicates rat METAP2 to be a target gene of ERα due to the half-ERE sites to be the candidate binding sites of ERα.The lower right panel demonstrates that DNA sequence of promoter region for mouse METAP2 (p67) includes two 5′ ERE half-sites and two 3′ ERE half-sites (D). This indicates mouse METAP2 to be a target gene of ERα due to the half-ERE sites to be the candidate binding sites of ERα.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3921136&req=5

f5-cin-13-2014-021: In vitro validation of an ERα target gene—METAP2 (p67).The upper left panel shows the results of western blot analysis on protein expression levels of METAP2 (p67) in MCF-7 cell model (A).Western blot analysis for METAP2 encoded protein indicates it to be regulated by ERα. We found increased p67 protein in MCF-7 with E2 treatment as compared to that with fulvestrant (ICI 182, 780 or ICI) treatment, (ICI + E2) treatment and control. MCF-7 cells were deprived of estrogen for 2 days and treated with 10−9 M E2 (labeled as + E2), 10−7 M ICI183,780 (labeled as + ICI183,780), or a combination of both (ICI + E2) for 48 hours. Total lysate (60 μg/lane) from MCF-7 cells was resolved in 7.5% SDS-PAGE and immunoblotted with anti-rat p67. β-actin was as the loading control. The lower blot was probed with anti-β-actin. The upper right panel shows that a diagram of the network prediction for interaction between ERα and STAT3 results in a switch in expression mode of their potential target gene-METAP2, which is predicted to be subtype relevant in ER(+) IDCs (B).Moreover, METAP2 is predicted to be shared target genes due to the combinatorial interaction of 2 given transcription factors (see the overlapping network of MYCnSTAT3 and ESR1nSTAT3 in Table S2.4 of Suppl. 2) but it is neither in the overlapping network of ESR1 and STAT3 nor in that of MYC and STAT3 (Table S2.6 in Suppl. 2). Based on the network analysis results, the proposed interplay between promoter use pathways of ESR1 nSTAT3 and MYCnSTAT3 in luminal A and B in regulating METAP2 is proposed (B).The lower left panel demonstrates that DNA sequence of promoter region for rat METAP2 (p67) (GenBank: U37710) includes 5 3′ ERE half-sites45 and a 5′Am2Tp2 variant site46 (C). This indicates rat METAP2 to be a target gene of ERα due to the half-ERE sites to be the candidate binding sites of ERα.The lower right panel demonstrates that DNA sequence of promoter region for mouse METAP2 (p67) includes two 5′ ERE half-sites and two 3′ ERE half-sites (D). This indicates mouse METAP2 to be a target gene of ERα due to the half-ERE sites to be the candidate binding sites of ERα.
Mentions: The STAT3 network is predicted to regulate only a subset of genes in the Warburg effect. Relatively low expression levels of LDHB and LDHA indicate that part of the Warburg effect may be suppressed in ER(+)BCs (Figs. 3C and 4B). In addition, MYC and STAT3 differentially regulate the expression of subunits for succinate dehydrogenase (SDH) that may alter the enzyme activities of SDH. However, the expression pattern of PC and GLS are conserved between ER(+) and ER(−) breast cancers (Figs. 5D9 and 3C). They do not follow the same regulatory route within the STAT3 transcriptional regulatory network. Based upon these results, the physiological role for high levels of LDHB, PC, SDHD and a transcript variant of MYC in non-tumor components could be of interest for future study.

Bottom Line: These data predict malignant events, treatment responses and a novel enhancer of tamoxifen resistance.Taken together, we identify a poor prognosis relevant gene set within the STAT3 network and a robust one in a subset of patients.VEGFA, ABL1, LYN, IGF2R and STAT3 are suggested therapeutic targets for further study based upon the degree of differential expression in our model.

View Article: PubMed Central - PubMed

Affiliation: Department of Agronomy, Biometry Division, National Taiwan University, Taipei, Taiwan.

ABSTRACT
The aberrantly expressed signal transducer and activator of transcription 3 (STAT3) predicts poor prognosis, primarily in estrogen receptor positive (ER(+)) breast cancers. Activated STAT3 is overexpressed in luminal A subtype cells. The mechanisms contributing to the prognosis and/or subtype relevant features of STAT3 in ER(+) breast cancers are through multiple interacting regulatory pathways, including STAT3-MYC, STAT3-ERα, and STAT3-MYC-ERα interactions, as well as the direct action of activated STAT3. These data predict malignant events, treatment responses and a novel enhancer of tamoxifen resistance. The inferred crosstalk between ERα and STAT3 in regulating their shared target gene-METAP2 is partially validated in the luminal B breast cancer cell line-MCF7. Taken together, we identify a poor prognosis relevant gene set within the STAT3 network and a robust one in a subset of patients. VEGFA, ABL1, LYN, IGF2R and STAT3 are suggested therapeutic targets for further study based upon the degree of differential expression in our model.

No MeSH data available.


Related in: MedlinePlus