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The Functional Crosstalk between HER2 Tyrosine Kinase and TGF-β Signaling in Breast Cancer Malignancy.

Wang SE - J Signal Transduct (2011)

Bottom Line: TGF-β, in turn, potentiates oncogenic HER2 signaling by inducing shedding of the ErbB ligands and clustering of HER2 with integrins.In addition, TGF-β is associated with resistance to trastuzumab, an anti-HER2 therapeutic antibody.Recent mechanistic studies indicate that TGF-β and HER2 cooperate through both Smad-dependent and independent mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, KCRB-2007, 1500 East Duarte Road, Duarte, CA 91010, USA.

ABSTRACT
Accumulating evidence indicates a functional crosstalk between the HER2 (ErbB2) tyrosine kinase and the TGF-β signaling mediated by its serine/threonine kinase receptors. In HER2-overexpressing breast cancer, this crosstalk results in increased cancer cell proliferation, survival and invasion, accelerated cancer progression and metastasis in animal models, and resistance to chemotherapy and HER2-targeted therapy. The transformed cellular context with constitutively active HER2 signaling, as a consequence of HER2 gene amplification or overexpression, converts TGF-β from a tumor suppressor to a malignancy-promoting factor. TGF-β, in turn, potentiates oncogenic HER2 signaling by inducing shedding of the ErbB ligands and clustering of HER2 with integrins. In addition, TGF-β is associated with resistance to trastuzumab, an anti-HER2 therapeutic antibody. Recent mechanistic studies indicate that TGF-β and HER2 cooperate through both Smad-dependent and independent mechanisms. Blockade of HER2:TGF-β crosstalk may significantly enhance the efficiency of conventional therapies in breast cancer patients with HER2 overexpression.

No MeSH data available.


Related in: MedlinePlus

Alk5TD signature is associated with clinical outcome in women with breast cancer (figure adapted from [27]).  (a) Hierarchical clustering of 295 breast tumors [28, 29] using 90 overlapping genes with the 271-gene Alk5TD signature.  (b) Kaplan Meier plots for recurrence-free survival (RFS) and overall survival (OS) comparing the two groups of tumors with and without a correlation with the Alk5TD signature.  (c) Hierarchical clustering of 22 breast tumors from patients who were treated with navelbine and trastuzumab [30] using 190 overlapping genes with the 271-gene Alk5TD signature. Cluster 2 shows a positive correlation with the Alk5TD signature. (d) Box-and-Whisker plot of standard pearson correlation between the Alk5TD signature and clusters determined in (c).
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fig2: Alk5TD signature is associated with clinical outcome in women with breast cancer (figure adapted from [27]). (a) Hierarchical clustering of 295 breast tumors [28, 29] using 90 overlapping genes with the 271-gene Alk5TD signature. (b) Kaplan Meier plots for recurrence-free survival (RFS) and overall survival (OS) comparing the two groups of tumors with and without a correlation with the Alk5TD signature. (c) Hierarchical clustering of 22 breast tumors from patients who were treated with navelbine and trastuzumab [30] using 190 overlapping genes with the 271-gene Alk5TD signature. Cluster 2 shows a positive correlation with the Alk5TD signature. (d) Box-and-Whisker plot of standard pearson correlation between the Alk5TD signature and clusters determined in (c).

Mentions: To understand the clinical relevance of the HER2:TGF-β crosstalk, we mapped an Alk5T204D-induced gene expression signature to a previously published 295-array data set by van de Vijver et al. [29] and Chang et al. [28]. The Alk5TD signature reflects biological and clinical differences in the 295 tumors. The tumors with a positive correlation with the active TβRI signature are mostly HER2 positive, Basal-like, and some Luminal B tumors while the tumors with a negative correlation are predominantly Luminal A and normal-like tumors (Figure 2(a)) [27]. Cancers with a positive correlation with the Alk5TD signature show a worse recurrence-free survival (RFS) and overall survival (OS) compared to tumors with a negative correlation (Figure 2(b)). We further explored possible correlation of the Alk5TD signature with resistance to trastuzumab by mapping this gene expression signature to an array data set reported by Harris et al. [30] obtained from 22 patients with HER2-overexpressing breast cancer treated with neoadjuvant trastuzumab and vinorelbine. Hierarchical clustering analysis shows that all 3 patients who achieved pathological complete response do not share similar expression with the TGF-β signature (Figures 2(c) and 2(d)) [27], which supports a role of TGF-β in inducing clinical resistance to trastuzumab.


The Functional Crosstalk between HER2 Tyrosine Kinase and TGF-β Signaling in Breast Cancer Malignancy.

Wang SE - J Signal Transduct (2011)

Alk5TD signature is associated with clinical outcome in women with breast cancer (figure adapted from [27]).  (a) Hierarchical clustering of 295 breast tumors [28, 29] using 90 overlapping genes with the 271-gene Alk5TD signature.  (b) Kaplan Meier plots for recurrence-free survival (RFS) and overall survival (OS) comparing the two groups of tumors with and without a correlation with the Alk5TD signature.  (c) Hierarchical clustering of 22 breast tumors from patients who were treated with navelbine and trastuzumab [30] using 190 overlapping genes with the 271-gene Alk5TD signature. Cluster 2 shows a positive correlation with the Alk5TD signature. (d) Box-and-Whisker plot of standard pearson correlation between the Alk5TD signature and clusters determined in (c).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3101605&req=5

fig2: Alk5TD signature is associated with clinical outcome in women with breast cancer (figure adapted from [27]). (a) Hierarchical clustering of 295 breast tumors [28, 29] using 90 overlapping genes with the 271-gene Alk5TD signature. (b) Kaplan Meier plots for recurrence-free survival (RFS) and overall survival (OS) comparing the two groups of tumors with and without a correlation with the Alk5TD signature. (c) Hierarchical clustering of 22 breast tumors from patients who were treated with navelbine and trastuzumab [30] using 190 overlapping genes with the 271-gene Alk5TD signature. Cluster 2 shows a positive correlation with the Alk5TD signature. (d) Box-and-Whisker plot of standard pearson correlation between the Alk5TD signature and clusters determined in (c).
Mentions: To understand the clinical relevance of the HER2:TGF-β crosstalk, we mapped an Alk5T204D-induced gene expression signature to a previously published 295-array data set by van de Vijver et al. [29] and Chang et al. [28]. The Alk5TD signature reflects biological and clinical differences in the 295 tumors. The tumors with a positive correlation with the active TβRI signature are mostly HER2 positive, Basal-like, and some Luminal B tumors while the tumors with a negative correlation are predominantly Luminal A and normal-like tumors (Figure 2(a)) [27]. Cancers with a positive correlation with the Alk5TD signature show a worse recurrence-free survival (RFS) and overall survival (OS) compared to tumors with a negative correlation (Figure 2(b)). We further explored possible correlation of the Alk5TD signature with resistance to trastuzumab by mapping this gene expression signature to an array data set reported by Harris et al. [30] obtained from 22 patients with HER2-overexpressing breast cancer treated with neoadjuvant trastuzumab and vinorelbine. Hierarchical clustering analysis shows that all 3 patients who achieved pathological complete response do not share similar expression with the TGF-β signature (Figures 2(c) and 2(d)) [27], which supports a role of TGF-β in inducing clinical resistance to trastuzumab.

Bottom Line: TGF-β, in turn, potentiates oncogenic HER2 signaling by inducing shedding of the ErbB ligands and clustering of HER2 with integrins.In addition, TGF-β is associated with resistance to trastuzumab, an anti-HER2 therapeutic antibody.Recent mechanistic studies indicate that TGF-β and HER2 cooperate through both Smad-dependent and independent mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, KCRB-2007, 1500 East Duarte Road, Duarte, CA 91010, USA.

ABSTRACT
Accumulating evidence indicates a functional crosstalk between the HER2 (ErbB2) tyrosine kinase and the TGF-β signaling mediated by its serine/threonine kinase receptors. In HER2-overexpressing breast cancer, this crosstalk results in increased cancer cell proliferation, survival and invasion, accelerated cancer progression and metastasis in animal models, and resistance to chemotherapy and HER2-targeted therapy. The transformed cellular context with constitutively active HER2 signaling, as a consequence of HER2 gene amplification or overexpression, converts TGF-β from a tumor suppressor to a malignancy-promoting factor. TGF-β, in turn, potentiates oncogenic HER2 signaling by inducing shedding of the ErbB ligands and clustering of HER2 with integrins. In addition, TGF-β is associated with resistance to trastuzumab, an anti-HER2 therapeutic antibody. Recent mechanistic studies indicate that TGF-β and HER2 cooperate through both Smad-dependent and independent mechanisms. Blockade of HER2:TGF-β crosstalk may significantly enhance the efficiency of conventional therapies in breast cancer patients with HER2 overexpression.

No MeSH data available.


Related in: MedlinePlus