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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

Functional prediction on roles of STAT3 gene partners in STAT3 subnetworks of ER(+) IDCs.6 functional subnetworks in 90 A and 72 A cohorts are generated via (1) Predicted networks derived from overlapping genes in Venn diagrams of the STAT3 subnetworks in ER(+) breast cancer gene expression profiles from a 90 A cohort (A); (2) 4 feature functionalities (cell proliferation, sustained angiogenesis, the Warburg effect and ES-like phenotype) of the major STAT3 target genes in 2 STAT3 subnetworks are either commonly co-regulated by MYC (C) and/or differentially co-regulated by FOXC1 and/or ARNT (B and D) in the ER(+) IDCs. A subset of genes, which are predicted to be prognostic factors, is potentially regulated by multiple combined routes of MYC and STAT3, ARNT/HIF1α and STAT3, ARNT/HIF2α and STAT3 or STAT3 for ES-like phenotype (D). E stands for the FOXC1 subnetwork to be a part of activities in cell proliferation. The summary for prognostic features of the STAT3 subnetworks in 90 A cohort and 72 A cohort are shown in F. Solid/dashed lines stand for the specific pathway identified as significant/insignificant in gene expression relationship between a TF and a target gene. Each arrow points toward its downstream target. The combined routes toward the same target gene are labeled with the same color. Relative mRNA expression levels are shown in a color scale (A). Poor prognostic factors are marked by the red rings. Good prognostic factors are marked by the light blue rings. If a probe is not significant shown by Kaplan-Meier survival analysis, it is marked with dotted ring.
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f3-cin-13-2014-021: Functional prediction on roles of STAT3 gene partners in STAT3 subnetworks of ER(+) IDCs.6 functional subnetworks in 90 A and 72 A cohorts are generated via (1) Predicted networks derived from overlapping genes in Venn diagrams of the STAT3 subnetworks in ER(+) breast cancer gene expression profiles from a 90 A cohort (A); (2) 4 feature functionalities (cell proliferation, sustained angiogenesis, the Warburg effect and ES-like phenotype) of the major STAT3 target genes in 2 STAT3 subnetworks are either commonly co-regulated by MYC (C) and/or differentially co-regulated by FOXC1 and/or ARNT (B and D) in the ER(+) IDCs. A subset of genes, which are predicted to be prognostic factors, is potentially regulated by multiple combined routes of MYC and STAT3, ARNT/HIF1α and STAT3, ARNT/HIF2α and STAT3 or STAT3 for ES-like phenotype (D). E stands for the FOXC1 subnetwork to be a part of activities in cell proliferation. The summary for prognostic features of the STAT3 subnetworks in 90 A cohort and 72 A cohort are shown in F. Solid/dashed lines stand for the specific pathway identified as significant/insignificant in gene expression relationship between a TF and a target gene. Each arrow points toward its downstream target. The combined routes toward the same target gene are labeled with the same color. Relative mRNA expression levels are shown in a color scale (A). Poor prognostic factors are marked by the red rings. Good prognostic factors are marked by the light blue rings. If a probe is not significant shown by Kaplan-Meier survival analysis, it is marked with dotted ring.

Mentions: In addition, STAT3 with different TF partner pools among different subtypes may offer another mechanism for predicting prognostic features of STAT3 in different subtypes (Fig. 3F, Tables 2 and 3), based on results in Figures 1 and 2, STAT3 may play a central role in ER(+) IDCs similar to that in ER(−) IDCs.9


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)

Functional prediction on roles of STAT3 gene partners in STAT3 subnetworks of ER(+) IDCs.6 functional subnetworks in 90 A and 72 A cohorts are generated via (1) Predicted networks derived from overlapping genes in Venn diagrams of the STAT3 subnetworks in ER(+) breast cancer gene expression profiles from a 90 A cohort (A); (2) 4 feature functionalities (cell proliferation, sustained angiogenesis, the Warburg effect and ES-like phenotype) of the major STAT3 target genes in 2 STAT3 subnetworks are either commonly co-regulated by MYC (C) and/or differentially co-regulated by FOXC1 and/or ARNT (B and D) in the ER(+) IDCs. A subset of genes, which are predicted to be prognostic factors, is potentially regulated by multiple combined routes of MYC and STAT3, ARNT/HIF1α and STAT3, ARNT/HIF2α and STAT3 or STAT3 for ES-like phenotype (D). E stands for the FOXC1 subnetwork to be a part of activities in cell proliferation. The summary for prognostic features of the STAT3 subnetworks in 90 A cohort and 72 A cohort are shown in F. Solid/dashed lines stand for the specific pathway identified as significant/insignificant in gene expression relationship between a TF and a target gene. Each arrow points toward its downstream target. The combined routes toward the same target gene are labeled with the same color. Relative mRNA expression levels are shown in a color scale (A). Poor prognostic factors are marked by the red rings. Good prognostic factors are marked by the light blue rings. If a probe is not significant shown by Kaplan-Meier survival analysis, it is marked with dotted ring.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3921136&req=5

f3-cin-13-2014-021: Functional prediction on roles of STAT3 gene partners in STAT3 subnetworks of ER(+) IDCs.6 functional subnetworks in 90 A and 72 A cohorts are generated via (1) Predicted networks derived from overlapping genes in Venn diagrams of the STAT3 subnetworks in ER(+) breast cancer gene expression profiles from a 90 A cohort (A); (2) 4 feature functionalities (cell proliferation, sustained angiogenesis, the Warburg effect and ES-like phenotype) of the major STAT3 target genes in 2 STAT3 subnetworks are either commonly co-regulated by MYC (C) and/or differentially co-regulated by FOXC1 and/or ARNT (B and D) in the ER(+) IDCs. A subset of genes, which are predicted to be prognostic factors, is potentially regulated by multiple combined routes of MYC and STAT3, ARNT/HIF1α and STAT3, ARNT/HIF2α and STAT3 or STAT3 for ES-like phenotype (D). E stands for the FOXC1 subnetwork to be a part of activities in cell proliferation. The summary for prognostic features of the STAT3 subnetworks in 90 A cohort and 72 A cohort are shown in F. Solid/dashed lines stand for the specific pathway identified as significant/insignificant in gene expression relationship between a TF and a target gene. Each arrow points toward its downstream target. The combined routes toward the same target gene are labeled with the same color. Relative mRNA expression levels are shown in a color scale (A). Poor prognostic factors are marked by the red rings. Good prognostic factors are marked by the light blue rings. If a probe is not significant shown by Kaplan-Meier survival analysis, it is marked with dotted ring.
Mentions: In addition, STAT3 with different TF partner pools among different subtypes may offer another mechanism for predicting prognostic features of STAT3 in different subtypes (Fig. 3F, Tables 2 and 3), based on results in Figures 1 and 2, STAT3 may play a central role in ER(+) IDCs similar to that in ER(−) IDCs.9

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