Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer.
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.
Bierie
Brian
B
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
Chung
Christine H
CH
Parker
Joel S
JS
Stover
Daniel G
DG
Cheng
Nikki
N
Chytil
Anna
A
Aakre
Mary
M
Shyr
Yu
Y
Moses
Harold L
HL
D000957:Antigens, Viral, Tumor / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D018925:Chemokines / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D011120:Polyomavirus / Q000276:immunology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000957:Antigens, Viral, Tumor; D018925:Chemokines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II