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Abrogation of TGF-beta 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-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.

SUBMITTER: Bierie B

PROVIDER: S-EPMC2689133 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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

Bierie Brian B 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

The Journal of clinical investigation 20090518 6

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-tumo ...[more]

PMID: 19451693

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Project description:BackgroundTransforming growth factor (TGF)-β signaling pathway, may act both as a tumor suppressor and as a tumor promoter in pancreatic cancer, depending on tumor stage and cellular context. TGF-β pathway has been under intensive investigation as a potential therapeutic target in the treatment of cancer. We hypothesized a correlation between TGF-βR2/SMAD4 expression in the tumor, plasma TGF-β1 ligand level, genetic variation in TGF-B pathway and prognosis of pancreatic cancer.MethodWe examined TGF-βR2 and SMAD4 protein expression in biopsy or surgical samples from 91 patients with pancreatic ductal adenocarcinoma (PDAC) using immunohistochemistry. Plasma level of TGF-β1 was measured in 644 patients with PDAC using ELISA. Twenty-eight single nucleotide polymorphisms (SNP) of the TGF-β1, TGF-β2, TGF-β3, TGF-βR1, TGF-βR2, and SMAD4 genes were determined in 1636 patients with PDAC using the Sequenom method. Correlation between protein expression in the tumor, plasma TGF-β1 level, and genotypes with overall survival (OS) was evaluated with Cox proportional regression models.ResultsThe expression level of TGF-βR2 and SMAD4 as an independent marker was not associated with OS. However, patients with both low nuclear staining of TGF-βR2 and high nuclear staining of SMAD4 may have better survival (P = 0.06). The mean and median level of TGF-β1 was 15.44 (SD: 10.99) and 12.61 (interquartile range: 8.31 to 19.04) ng/ml respectively. Patients with advanced disease and in the upper quartile range of TGF-β1 level had significantly reduced survival than those with low levels (P = 0.02). A significant association of SMAD4 SNP rs113545983 with overall survival was observed (P<0.0001).ConclusionOur data provides valuable baseline information regarding the TGF-β pathway in pancreatic cancer, which can be utilized in targeted therapy clinical trials. High TGF-β1 plasma level, SMAD4 SNP or TGF-βR2/SMAD4 tumor protein expression may suggest a dependence on this pathway in patients with advanced pancreatic cancer.

Project description:Specific deletion of Tgfbr2 in FSP1+ fibroblasts (Tgfbr2fspKO) induced development of SCC in forestomach with 100% penetrance. Tgfbr2fspKO mice die by 7 weeks with a median survival of 38 days (Log rank p<0.001). Examination of Tgfbr2fspKO forestomach between embryonic day 16 (E16) and 5 weeks of age suggested that hyperplasia began during week 3 and was followed by dysplasia, carcinoma in situ, and invasive squamous cell carcinoma (SCC). The aim of this study was to elucidate genetic aberrations in the tumor associated stroma and SCC tumor using array comparative genomic hybridization (CGH) analysis. Laser capture micro-dissection was performed using formalin-fixed, paraffin-embedded, 5 week old Tgfbr2fspKO forestomach tissues. Genetic loss of cyclin-dependent kinase inhibitor, Cdkn2a/ p16Ink4A was found in laser captured epithelia of all three Tgfbr2fspKO forestomachs. Surprisingly, no genetic change was seen in the tumor associated stroma. Examination of human esophageal SCC showed a down-regulation of TGFβ receptor 2 (TβRII) in the stromal fibroblasts as well as increased inflammation and DNA damage. Published literature showed that loss of Cdkn2a/p16Ink4A tumor suppressor is the common event in human ESCCs. Our study suggests anti-inflammation may be a new therapeutic option in treating human SCCs with down-regulation of TβRII in the stroma. Laser capture microdissection of Tgfbr2flox/flox (n=3) and Tgfbr2fspKO (n=3) forestomach tissues was performed using an Arcturus XT (Life Technologies, CA, USA). Mouse background strain is C57Bl6. Frozen tissue sections on PEN membrane frame slides (Applied Biosystems) were H&E stained followed by dehydration using the standard protocol to improve visualization of the cells at the microscope. The epithelia and stroma were identified by morphology, captured using a low-power infrared laser pulse, and transferred onto a cap (Capsure™ Macro LCM Caps, Life Technologies). The DNA was extracted using a QIAamp DNA micro kit (Qiagen, CA, USA). Array-CGH was performed using test DNA from laser captured epithelia and stroma from Tgfbr2fspKO mice. Reference DNA was laser captured from the epithelia of normal forestomach of Tgfbr2flox/flox mice. DNA was labeled with Cy3 (test) or Cy5 (control) fluorescent dyes (Perkin Elmer, MA, USA) according to the BioPrime array CGH genomic labeling protocol (Invitrogen, Carlsbad, CA) and cleaned using Microcon YM-30 filters (Millipore, Billerica, MA). Hybridization was carried out using Mouse Genome CGH Microarray 4x180 K format from Agilent Technologies (Santa Clara, CA) according to CGH Procedures for Genomic DNA Analysis (Agilent Technologies). Slides were hybridized for 20 hours, washed, and scanned with an Agilent microarray scanner. Data was analyzed using Feature Extraction® and CGH Analytics® software packages (Agilent Technologies).

Dataset Information

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

Publications

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

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