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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

Heatmaps for the subnetworks of MYC and STAT3 and the proposed TAM resistance mechanism.We described the levels of gene expression for both ERα and STAT3 by coloring with green for low and blue for high. The thickness of line indicates the degree of activities that are predicted to depend on the expression level of ERα when STAT3 is elevated in triple negatives and ER(+) infiltrating ductal breast carcinomas.ERα is weakly expressed in triple negatives. Thus, it is possible that crosstalk between ERα and STAT3 in TN is relatively weak. To this subset of patients, TAM treatment is not applied as one of the cancer therapies. On the other hand, the high possibility of TAM resistance in a subset of luminal A is proposed. The proposed mechanism of TAM resistance due to crosstalk between ERα and STAT3 has been described in the main text. Figures 7A and B show the gene profilings of ERBB2 signaling molecules predicted to be regulated by STAT3 in coupling with MYC in triple negatives/ERBB2+, groups IE/IIE, respectively. Two corresponding non-tumor (NT) components are as the control gene profilings in this case (A and B).Both MYC and STAT3 differentially up-regulate the mRNA expression for a subset of ERBB2 signaling molecules among and/or within subtypes (A and B). The estrogen action on crosstalk between ERα and STAT3 is mainly seen in luminal A (see arrows with thick lines colored with orange or dark blue in Fig. 7D) but is weak in TN (see arrows with thin lines colored with orange or dark blue in Fig. 7C). We describe phosphorylation at serine/threonine residues (The p is high-lighted by orange color), tyrosine residues (The p is high-lighted by yellow color) and the mixed types (The p is not high-lighted). (C and D) are summarized from current review articles10,18 with a few modifications derived from our findings. In Figures 7C and D, the example of the most relevant target genes of STAT3 and/or ERα are from our findings in Tables S1.4, S2.1, S2.3, S2.4 and S2.6.
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f7-cin-13-2014-021: Heatmaps for the subnetworks of MYC and STAT3 and the proposed TAM resistance mechanism.We described the levels of gene expression for both ERα and STAT3 by coloring with green for low and blue for high. The thickness of line indicates the degree of activities that are predicted to depend on the expression level of ERα when STAT3 is elevated in triple negatives and ER(+) infiltrating ductal breast carcinomas.ERα is weakly expressed in triple negatives. Thus, it is possible that crosstalk between ERα and STAT3 in TN is relatively weak. To this subset of patients, TAM treatment is not applied as one of the cancer therapies. On the other hand, the high possibility of TAM resistance in a subset of luminal A is proposed. The proposed mechanism of TAM resistance due to crosstalk between ERα and STAT3 has been described in the main text. Figures 7A and B show the gene profilings of ERBB2 signaling molecules predicted to be regulated by STAT3 in coupling with MYC in triple negatives/ERBB2+, groups IE/IIE, respectively. Two corresponding non-tumor (NT) components are as the control gene profilings in this case (A and B).Both MYC and STAT3 differentially up-regulate the mRNA expression for a subset of ERBB2 signaling molecules among and/or within subtypes (A and B). The estrogen action on crosstalk between ERα and STAT3 is mainly seen in luminal A (see arrows with thick lines colored with orange or dark blue in Fig. 7D) but is weak in TN (see arrows with thin lines colored with orange or dark blue in Fig. 7C). We describe phosphorylation at serine/threonine residues (The p is high-lighted by orange color), tyrosine residues (The p is high-lighted by yellow color) and the mixed types (The p is not high-lighted). (C and D) are summarized from current review articles10,18 with a few modifications derived from our findings. In Figures 7C and D, the example of the most relevant target genes of STAT3 and/or ERα are from our findings in Tables S1.4, S2.1, S2.3, S2.4 and S2.6.

Mentions: It is of interest that the sustained angiogenesis network in ER(+) BCs shares the same architecture with ER(−) BCs (Figs. 5C9 and 3B) except that FOXC1 is an additional partner of STAT3 (Fig. 3B, Tables S1.10 and S1.11). Importantly, we found that the mechanism for sustained angiogenesis driven by the STAT3 network in ER(−) BCs (Fig. 7B9) is partially relevant in ER(+) BCs (Fig. 3B). This may suggest that different transcriptional regulators interact with STAT3 to control tumor angiogenesis dependent upon different BC subtypes. Other in vitro studies29,30 support the concept that FOXC1, ARNT and FOXC2 are transcriptional regulators in angiogenesis. Further investigations of co-regulatory subnetworks involving these transcription factors and their relationship with patient angiosonograms will be explored in the future. Figure 6 shows that 43.75% of sonograms do not match with the gene expression signature of sustained angiogenesis based upon heatmaps. This could be due to limitations in sampling of gene expression profiles that reduce the accuracy of prediction9 or an alternative mechanism(s) controlling sustained angiogenesis. Therefore, more regulatory components of sustained angiogenesis are expected to be discovered in vitro, in vivo and in silico.


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)

Heatmaps for the subnetworks of MYC and STAT3 and the proposed TAM resistance mechanism.We described the levels of gene expression for both ERα and STAT3 by coloring with green for low and blue for high. The thickness of line indicates the degree of activities that are predicted to depend on the expression level of ERα when STAT3 is elevated in triple negatives and ER(+) infiltrating ductal breast carcinomas.ERα is weakly expressed in triple negatives. Thus, it is possible that crosstalk between ERα and STAT3 in TN is relatively weak. To this subset of patients, TAM treatment is not applied as one of the cancer therapies. On the other hand, the high possibility of TAM resistance in a subset of luminal A is proposed. The proposed mechanism of TAM resistance due to crosstalk between ERα and STAT3 has been described in the main text. Figures 7A and B show the gene profilings of ERBB2 signaling molecules predicted to be regulated by STAT3 in coupling with MYC in triple negatives/ERBB2+, groups IE/IIE, respectively. Two corresponding non-tumor (NT) components are as the control gene profilings in this case (A and B).Both MYC and STAT3 differentially up-regulate the mRNA expression for a subset of ERBB2 signaling molecules among and/or within subtypes (A and B). The estrogen action on crosstalk between ERα and STAT3 is mainly seen in luminal A (see arrows with thick lines colored with orange or dark blue in Fig. 7D) but is weak in TN (see arrows with thin lines colored with orange or dark blue in Fig. 7C). We describe phosphorylation at serine/threonine residues (The p is high-lighted by orange color), tyrosine residues (The p is high-lighted by yellow color) and the mixed types (The p is not high-lighted). (C and D) are summarized from current review articles10,18 with a few modifications derived from our findings. In Figures 7C and D, the example of the most relevant target genes of STAT3 and/or ERα are from our findings in Tables S1.4, S2.1, S2.3, S2.4 and S2.6.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f7-cin-13-2014-021: Heatmaps for the subnetworks of MYC and STAT3 and the proposed TAM resistance mechanism.We described the levels of gene expression for both ERα and STAT3 by coloring with green for low and blue for high. The thickness of line indicates the degree of activities that are predicted to depend on the expression level of ERα when STAT3 is elevated in triple negatives and ER(+) infiltrating ductal breast carcinomas.ERα is weakly expressed in triple negatives. Thus, it is possible that crosstalk between ERα and STAT3 in TN is relatively weak. To this subset of patients, TAM treatment is not applied as one of the cancer therapies. On the other hand, the high possibility of TAM resistance in a subset of luminal A is proposed. The proposed mechanism of TAM resistance due to crosstalk between ERα and STAT3 has been described in the main text. Figures 7A and B show the gene profilings of ERBB2 signaling molecules predicted to be regulated by STAT3 in coupling with MYC in triple negatives/ERBB2+, groups IE/IIE, respectively. Two corresponding non-tumor (NT) components are as the control gene profilings in this case (A and B).Both MYC and STAT3 differentially up-regulate the mRNA expression for a subset of ERBB2 signaling molecules among and/or within subtypes (A and B). The estrogen action on crosstalk between ERα and STAT3 is mainly seen in luminal A (see arrows with thick lines colored with orange or dark blue in Fig. 7D) but is weak in TN (see arrows with thin lines colored with orange or dark blue in Fig. 7C). We describe phosphorylation at serine/threonine residues (The p is high-lighted by orange color), tyrosine residues (The p is high-lighted by yellow color) and the mixed types (The p is not high-lighted). (C and D) are summarized from current review articles10,18 with a few modifications derived from our findings. In Figures 7C and D, the example of the most relevant target genes of STAT3 and/or ERα are from our findings in Tables S1.4, S2.1, S2.3, S2.4 and S2.6.
Mentions: It is of interest that the sustained angiogenesis network in ER(+) BCs shares the same architecture with ER(−) BCs (Figs. 5C9 and 3B) except that FOXC1 is an additional partner of STAT3 (Fig. 3B, Tables S1.10 and S1.11). Importantly, we found that the mechanism for sustained angiogenesis driven by the STAT3 network in ER(−) BCs (Fig. 7B9) is partially relevant in ER(+) BCs (Fig. 3B). This may suggest that different transcriptional regulators interact with STAT3 to control tumor angiogenesis dependent upon different BC subtypes. Other in vitro studies29,30 support the concept that FOXC1, ARNT and FOXC2 are transcriptional regulators in angiogenesis. Further investigations of co-regulatory subnetworks involving these transcription factors and their relationship with patient angiosonograms will be explored in the future. Figure 6 shows that 43.75% of sonograms do not match with the gene expression signature of sustained angiogenesis based upon heatmaps. This could be due to limitations in sampling of gene expression profiles that reduce the accuracy of prediction9 or an alternative mechanism(s) controlling sustained angiogenesis. Therefore, more regulatory components of sustained angiogenesis are expected to be discovered in vitro, in vivo and in silico.

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