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J Clin Invest. 2009 Jun;119(6):1571-82. doi: 10.1172/JCI37480. Epub 2009 May 18.

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

Author information

1
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.

Abstract

In human breast cancer, loss of carcinoma cell-specific response to TGF-beta signaling has been linked to poor patient prognosis. However, the mechanisms through which TGF-beta regulates these processes remain largely unknown. In an effort to address this issue, we have now identified gene expression signatures associated with the TGF-beta signaling pathway in human mammary carcinoma cells. The results strongly suggest that TGF-beta 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-beta-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-beta 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-beta signaling pathway status may further stratify the prognosis of ER-positive patients and provide novel therapeutic approaches in the management of breast cancer.

PMID:
19451693
PMCID:
PMC2689133
DOI:
10.1172/JCI37480
[Indexed for MEDLINE]
Free PMC Article

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