Abrogation of TGF-β signaling enhances chemokine production and correlates with prognosis in human breast cancer
Brian Bierie, Christine H. Chung, Joel S. Parker, Daniel G. Stover, Nikki Cheng, Anna Chytil, Mary Aakre, Yu Shyr, Harold L. Moses
Brian Bierie, Christine H. Chung, Joel S. Parker, Daniel G. Stover, Nikki Cheng, Anna Chytil, Mary Aakre, Yu Shyr, Harold L. Moses
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Research Article Oncology

Abrogation of TGF-β signaling enhances chemokine production and correlates with prognosis in human breast cancer

Abstract

In human breast cancer, loss of carcinoma cell–specific response to TGF-β signaling has been linked to poor patient prognosis. However, the mechanisms through which TGF-β regulates these processes remain largely unknown. In an effort to address this issue, we have now identified gene expression signatures associated with the TGF-β signaling pathway in human mammary carcinoma cells. The results strongly suggest that TGF-β signaling mediates intrinsic, stromal-epithelial, and host-tumor interactions during breast cancer progression, at least in part, by regulating basal and oncostatin M–induced CXCL1, CXCL5, and CCL20 chemokine expression. To determine the clinical relevance of our results, we queried our TGF-β–associated gene expression signatures in 4 human breast cancer data sets containing a total of 1,319 gene expression profiles and associated clinical outcome data. The signature representing complete abrogation of TGF-β signaling correlated with reduced relapse-free survival in all patients; however, the strongest association was observed in patients with estrogen receptor–positive (ER-positive) tumors, specifically within the luminal A subtype. Together, the results suggest that assessment of TGF-β signaling pathway status may further stratify the prognosis of ER-positive patients and provide novel therapeutic approaches in the management of breast cancer.

Authors

Brian Bierie, Christine H. Chung, Joel S. Parker, Daniel G. Stover, Nikki Cheng, Anna Chytil, Mary Aakre, Yu Shyr, Harold L. Moses

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Figure 4

Loss of TGF-β signaling in mammary carcinoma cells resulted in a signature that correlated with increased risk of relapse during human breast cancer progression.

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Loss of TGF-β signaling in mammary carcinoma cells resulted in a signatu...
(A) The TGF-β signature correlation with breast cancer RFS in all patients. TβRII(WKO;PY) and TβRII(fl/fl;PY) mammary carcinoma gene expression signatures were compared with profiles from 1,319 human breast cancer tissues. The TβRII(WKO;PY) and TβRII(fl/fl;PY) plus TGF-β treatment signatures were also used to determine the correlation with RFS (left and right columns, respectively). The TβRII(WKO;PY) signature significantly correlated with decreased RFS. No significant difference in RFS was observed in correlation with the TGF-β treatment gene expression signature. (B) In human LN+ breast cancer patients, the TβRII(WKO;PY) signature correlated with reduced RFS (left), whereas the TGF-β treatment signature did not have a significant correlation (right). (C) In LN– patients, no significant correlations were observed. Red, high correlation (r > 0); black, low correlation (r < 0). The “high versus low” model is based on transforming the TGF-β signature correlation into a dichotomous variable (high: r > 0; low: r < 0), and the “continuous” model uses the untransformed correlation as a continuous variable. Association of these groups with RFS was evaluated with the log-rank test.