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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

Model. There is a potential link between IL6-pSTAT3-PTEN loss, stromal reactivation, and primary trastuzumab resistance in HER2-positive primary breast cancers
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Fig4: Model. There is a potential link between IL6-pSTAT3-PTEN loss, stromal reactivation, and primary trastuzumab resistance in HER2-positive primary breast cancers

Mentions: Overall, we propose that the STAT3-stromal feed-forward loop, which can be enhanced by PTEN loss, is predictive of primary trastuzumab resistance (model; Fig. 4). If confirmed by future large prospective, randomized, controlled studies, inhibiting the IL6-STAT3 pathway [33] may be a valuable addition to trastuzumab treatment of primary HER2-positive breast cancer, especially those that are PTEN deficient.Fig. 4


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)

Model. There is a potential link between IL6-pSTAT3-PTEN loss, stromal reactivation, and primary trastuzumab resistance in HER2-positive primary breast cancers
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522972&req=5

Fig4: Model. There is a potential link between IL6-pSTAT3-PTEN loss, stromal reactivation, and primary trastuzumab resistance in HER2-positive primary breast cancers
Mentions: Overall, we propose that the STAT3-stromal feed-forward loop, which can be enhanced by PTEN loss, is predictive of primary trastuzumab resistance (model; Fig. 4). If confirmed by future large prospective, randomized, controlled studies, inhibiting the IL6-STAT3 pathway [33] may be a valuable addition to trastuzumab treatment of primary HER2-positive breast cancer, especially those that are PTEN deficient.Fig. 4

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