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 2

TGF-β–dependent chemokine protein secretion by mammary carcinoma cells and the effect of Cxcl1 stimulation on metastatic mammary carcinoma cell migration.

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TGF-β–dependent chemokine protein secretion by mammary carcinoma cells a...
(A) Conditioned medium from TβRII(WKO;PY) and TβRII(fl/fl;PY) mammary carcinoma cells revealed increased secretion of Cxcl1 and Cxcl5 protein by the TβRII(WKO;PY) populations according to cytokine antibody array. Quantitation of Cxcl1 and Cxcl5 expression was performed and represented as the median transformed mean values ± SEM. P < 0.05, TβRII(WKO;PY) (KO) vs. TβRII(fl/fl;PY) (Ctl), 2-tailed unpaired t test. (B) Wound closure assays were used to determine the effect of Cxcl1 presence on metastatic carcinoma cell migration. Cxcr2 protein production by the 4T1 cell line was observed by Western blot (WB), and the expression of CXCR2 by MDA-MD-231 cells has been previously reported (38–40). Values are reported as mean percentage ± SEM. For the 4T1 carcinoma cell line, P = 0.5018 at 5 ng/ml, P = 0.0853 at 20 ng/ml, P = 0.0588 at 40 ng/ml, P < 0.005 at 80 ng/ml, 2-tailed unpaired t test. For the MDA-MB-231 cell line: P = 0.0019 at 5 ng/ml, P = 0.0411 at 20 ng/ml, and P = 0.0068 at 40 ng/ml, 2-tailed, unpaired t test.