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

Bierie B, Chung CH, Parker JS, Stover DG, Cheng N, Chytil A, Aakre M, Shyr Y, Moses HL
J Clin Invest. 2009 119 (6): 1571-82

PMID: 19451693 · PMCID: PMC2689133 · DOI:10.1172/JCI37480

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.

MeSH Terms (16)

Antigens, Viral, Tumor Breast Neoplasms Cell Differentiation Cell Line, Tumor Chemokines Epithelial Cells Gene Expression Regulation, Neoplastic Humans Polyomavirus Prognosis Protein-Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta Signal Transduction Stem Cells Transforming Growth Factor beta

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