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Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer.

Sonnenblick A, Brohée S, Fumagalli D, Vincent D, Venet D, Ignatiadis M, Salgado R, Van den Eynden G, Rothé F, Desmedt C, Neven P, Loibl S, Denkert C, Joensuu H, Loi S, Sirtaine N, Kellokumpu-Lehtinen PL, Piccart M, Sotiriou C - BMC Med (2015)

Bottom Line: Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways.We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02).These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02).

View Article: PubMed Central - PubMed

Affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.

ABSTRACT

Background: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance.

Methods: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting.

Results: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation.

Conclusions: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.

No MeSH data available.


Related in: MedlinePlus

pSTAT3 and pSTAT3-GS are associated with PTEN loss and stromal reactivation. a pSTAT3 is associated with PTEN loss. Heatmap representation of the correlations between the RPPA values in the Responsify dataset. Cells are colored according to Pearson correlation coefficient values, with green indicating positive correlation and red negative correlations. b pSTAT3-GS is associated with stromal reactivation. The heatmap reflects the hierarchic clustering of pairwise correlations between different gene signatures in the Responsify dataset. Cells are colored according to Pearson correlation coefficient values, with green indicating positive correlation and red negative correlations. c The heatmap of the top significantly enriched genes in PAM50-identified patients with HER2-positive breast cancer annotated in the TCGA (P <0.001, fold >1), selected according to the high or low RPPA expression level of pSTAT3. Cells are colored according to the gene expression values, with green indicating positive correlation and red negative correlation. d pSTAT3-GS correlates with histological stromal reactivation. Histological sections showing breast tumors containing low (+), intermediate (++), and high (+++) reactive stroma. Heatmap shows correlation of reactive stromal content with clinical pathological parameters (not significant) and correlation with different gene signatures including stromal signature and pSTAT3-GS. * Negative correlation, P values were assessed using Mann–Whitney test
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Fig3: pSTAT3 and pSTAT3-GS are associated with PTEN loss and stromal reactivation. a pSTAT3 is associated with PTEN loss. Heatmap representation of the correlations between the RPPA values in the Responsify dataset. Cells are colored according to Pearson correlation coefficient values, with green indicating positive correlation and red negative correlations. b pSTAT3-GS is associated with stromal reactivation. The heatmap reflects the hierarchic clustering of pairwise correlations between different gene signatures in the Responsify dataset. Cells are colored according to Pearson correlation coefficient values, with green indicating positive correlation and red negative correlations. c The heatmap of the top significantly enriched genes in PAM50-identified patients with HER2-positive breast cancer annotated in the TCGA (P <0.001, fold >1), selected according to the high or low RPPA expression level of pSTAT3. Cells are colored according to the gene expression values, with green indicating positive correlation and red negative correlation. d pSTAT3-GS correlates with histological stromal reactivation. Histological sections showing breast tumors containing low (+), intermediate (++), and high (+++) reactive stroma. Heatmap shows correlation of reactive stromal content with clinical pathological parameters (not significant) and correlation with different gene signatures including stromal signature and pSTAT3-GS. * Negative correlation, P values were assessed using Mann–Whitney test

Mentions: Considering studies that have suggested that STAT3 could participate in oncogenesis through the up-regulation of genes encoding cell-cycle regulators (cyclins D1, c-Myc), and a recent report of in vitro data suggesting that PTEN signaling may be associated with trastuzumab resistance [21], we sought to investigate whether there was any relationship at the protein level between pSTAT3, PTEN, and other proteins regulated by STAT3 in our clinical samples. Using RPPA (211 proteins) in the Responsify dataset, we found that pSTAT3 was negatively correlated with PTEN (r = –0.4, fdr = 0.025) and positively correlated with stathmin (r = 0.66, fdr = 0.03), a known marker of PTEN loss [22] (Fig. 3a). Other significant positive correlations with STAT3 included c-Myc (r = 0.39, fdr = 0.04), c-Kit (r = 0.66, fdr = 1.1e-5), and pEGFR (r = 0.52, fdr = 0.001). pcMET and cyclin D1 were also positively correlated, but did not pass the fdr ≤0.05 threshold. These data confirm that in primary HER2-positive breast cancer, STAT3 participates in oncogenesis through the up-regulation of genes encoding cell-cycle regulators and that PTEN loss may be associated with STAT3 activation.Fig. 3


Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer.

Sonnenblick A, Brohée S, Fumagalli D, Vincent D, Venet D, Ignatiadis M, Salgado R, Van den Eynden G, Rothé F, Desmedt C, Neven P, Loibl S, Denkert C, Joensuu H, Loi S, Sirtaine N, Kellokumpu-Lehtinen PL, Piccart M, Sotiriou C - BMC Med (2015)

pSTAT3 and pSTAT3-GS are associated with PTEN loss and stromal reactivation. a pSTAT3 is associated with PTEN loss. Heatmap representation of the correlations between the RPPA values in the Responsify dataset. Cells are colored according to Pearson correlation coefficient values, with green indicating positive correlation and red negative correlations. b pSTAT3-GS is associated with stromal reactivation. The heatmap reflects the hierarchic clustering of pairwise correlations between different gene signatures in the Responsify dataset. Cells are colored according to Pearson correlation coefficient values, with green indicating positive correlation and red negative correlations. c The heatmap of the top significantly enriched genes in PAM50-identified patients with HER2-positive breast cancer annotated in the TCGA (P <0.001, fold >1), selected according to the high or low RPPA expression level of pSTAT3. Cells are colored according to the gene expression values, with green indicating positive correlation and red negative correlation. d pSTAT3-GS correlates with histological stromal reactivation. Histological sections showing breast tumors containing low (+), intermediate (++), and high (+++) reactive stroma. Heatmap shows correlation of reactive stromal content with clinical pathological parameters (not significant) and correlation with different gene signatures including stromal signature and pSTAT3-GS. * Negative correlation, P values were assessed using Mann–Whitney test
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4522972&req=5

Fig3: pSTAT3 and pSTAT3-GS are associated with PTEN loss and stromal reactivation. a pSTAT3 is associated with PTEN loss. Heatmap representation of the correlations between the RPPA values in the Responsify dataset. Cells are colored according to Pearson correlation coefficient values, with green indicating positive correlation and red negative correlations. b pSTAT3-GS is associated with stromal reactivation. The heatmap reflects the hierarchic clustering of pairwise correlations between different gene signatures in the Responsify dataset. Cells are colored according to Pearson correlation coefficient values, with green indicating positive correlation and red negative correlations. c The heatmap of the top significantly enriched genes in PAM50-identified patients with HER2-positive breast cancer annotated in the TCGA (P <0.001, fold >1), selected according to the high or low RPPA expression level of pSTAT3. Cells are colored according to the gene expression values, with green indicating positive correlation and red negative correlation. d pSTAT3-GS correlates with histological stromal reactivation. Histological sections showing breast tumors containing low (+), intermediate (++), and high (+++) reactive stroma. Heatmap shows correlation of reactive stromal content with clinical pathological parameters (not significant) and correlation with different gene signatures including stromal signature and pSTAT3-GS. * Negative correlation, P values were assessed using Mann–Whitney test
Mentions: Considering studies that have suggested that STAT3 could participate in oncogenesis through the up-regulation of genes encoding cell-cycle regulators (cyclins D1, c-Myc), and a recent report of in vitro data suggesting that PTEN signaling may be associated with trastuzumab resistance [21], we sought to investigate whether there was any relationship at the protein level between pSTAT3, PTEN, and other proteins regulated by STAT3 in our clinical samples. Using RPPA (211 proteins) in the Responsify dataset, we found that pSTAT3 was negatively correlated with PTEN (r = –0.4, fdr = 0.025) and positively correlated with stathmin (r = 0.66, fdr = 0.03), a known marker of PTEN loss [22] (Fig. 3a). Other significant positive correlations with STAT3 included c-Myc (r = 0.39, fdr = 0.04), c-Kit (r = 0.66, fdr = 1.1e-5), and pEGFR (r = 0.52, fdr = 0.001). pcMET and cyclin D1 were also positively correlated, but did not pass the fdr ≤0.05 threshold. These data confirm that in primary HER2-positive breast cancer, STAT3 participates in oncogenesis through the up-regulation of genes encoding cell-cycle regulators and that PTEN loss may be associated with STAT3 activation.Fig. 3

Bottom Line: Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways.We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02).These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02).

View Article: PubMed Central - PubMed

Affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.

ABSTRACT

Background: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance.

Methods: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting.

Results: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation.

Conclusions: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.

No MeSH data available.


Related in: MedlinePlus