Prognostic significance of the expression of GFRα1, GFRα3 and Syndecan-3, proteins binding ARTEMIN, in mammary carcinoma

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Abstract

Background

Artemin (ARTN) has been implicated in promoting oncogenicity, tumor growth and invasiveness in diverse human malignancies. However, the clinical and prognostic significance of upstream ligand binding components, potentially mediating ARTN oncogenicity, largely remain to be determined.

Methods

We determined the mRNA and protein expression of three proteins demonstrated to bind ARTN, namely GFRα1, GFRα3 and Syndecan-3 (SDC3), in benign breast disease and mammary carcinoma by in situ hybridization and immunohistochemistry, respectively. Their prognostic significance combined with ARTN expression was also investigated in mammary carcinoma.

Results

The expression of GFRα1 and GFRα3, but not SDC3, was significantly increased in mammary carcinoma and positively associated with tumor lymph node metastases, higher clinical stage and HER-2 positivity. Moreover, both GFRα1 and GFRα3 expression were significantly associated with survival outcome of patients with mammary carcinoma by univariate and multivariate analyses, whereas expression of SDC3 was not. Co-expression of ARTN with either GFRα1 or GFRα3, but not SDC3, produced synergistic increases in the odds ratio for both relapse-free and overall survival in patients with mammary carcinoma. Furthermore, significant association of GFRα1 and GFRα3 expression with survival outcome observed herein were restricted to ER negative or HER-2 negative mammary carcinoma.

Conclusions

The expression of GFRα1 and/or GFRα3, especially when combined with ARTN expression, may be useful predictors of disease progression and outcome in specific subtypes of mammary carcinoma.

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Most cited references 21

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Prognostic significance of MMP-9 and TIMP-1 serum and tissue expression in breast cancer.

Zheng-Sheng Wu, Qiang Wu, Jiu-Hua Yang … (2008)

Tumor progression and metastasis contribute to the great majority of breast cancer deaths. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to be involved in tumor progression and metastasis. Thus, we determined whether the expression of MMP-9 and TIMP-1 is associated with prognosis in breast cancer patients. We measured serum MMP-9 and TIMP-1 by enzyme-linked immunosorbent assay in 60 breast cancer patients, 18 benign breast disease patients and 15 healthy controls. We also evaluated the expression of MMP-9 and TIMP-1 protein and mRNA in paraffin-embedded tumor tissues from the 60 breast cancer patients by immunohistochemistry and in situ hybridization. We then correlated serum and tissue levels of MMP-9 and TIMP-1 in breast cancer samples and their expression with patients' clinicopathologic characteristics. We found that serum levels of MMP-9 and TIMP-1 were significantly higher in breast cancer patients than in benign breast disease and in healthy controls. High serum levels of MMP-9 and TIMP-1 were associated with lymph node metastasis, higher tumor stage and lower relapse-free and overall survival (OS) rates. Compared to low expression, high tissue expression of MMP-9 protein was associated with lymph node metastasis and higher tumor stage; and high tissue expression of TIMP-1 was associated with a lower OS rate. Our findings suggest that MMP-9 and TIMP-1 may further be evaluated as biomarkers for predicting progression and prognosis of breast cancer. (c) 2008 Wiley-Liss, Inc.

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Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance.

Shelley Morandi, M Dowsett, Stacy S. Drury … (2010)

Endocrine therapy is the main therapeutic option for patients with estrogen receptor (ERalpha)-positive breast cancer. Resistance to this treatment is often associated with estrogen-independent activation of ERalpha. In this study, we show that in ERalpha-positive breast cancer cells, activation of the receptor tyrosine kinase RET (REarranged during Transfection) by its ligand GDNF results in increased ERalpha phosphorylation on Ser118 and Ser167 and estrogen-independent activation of ERalpha transcriptional activity. Further, we identify mTOR as a key component in this downstream signaling pathway. In tamoxifen response experiments, RET downregulation resulted in 6.2-fold increase in sensitivity of MCF7 cells to antiproliferative effects of tamoxifen, whereas GDNF stimulation had a protective effect against the drug. In tamoxifen-resistant (TAM(R)-1) MCF7 cells, targeting RET restored tamoxifen sensitivity. Finally, examination of two independent tissue microarrays of primary human breast cancers revealed that expression of RET protein was significantly associated with ERalpha-positive tumors and that in primary tumors from patients who subsequently developed invasive recurrence after adjuvant tamoxifen treatment, there was a twofold increase in the number of RET-positive tumors. Together these findings identify RET as a potentially important therapeutic target in ERalpha-positive breast cancers and in particular in tamoxifen-resistant tumors.

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Nerve growth factor and artemin are paracrine mediators of pancreatic neuropathy in pancreatic adenocarcinoma.

Güralp Ceyhan, N Giese, Mert Erkan … (2010)

To further characterize the neurotrophic attributes of pancreatic cancer (PCa). PCa is characterized by neuropathic alterations which are resulting in pancreatic pain. To further characterize pancreatic neuropathy, we aimed: to analyze whether neuropathic alterations in PCa are only limited to the tumor-core or whether they are similarly encountered in neural structures in the noncancerous pancreas, to demonstrate whether PCa features neurotrophic attributes and finally to identify responsible neurotrophic molecules. Nerve density and area were quantified in normal pancreas (NP, n=45), histologically "normal" pancreas next to pancreatic cancer (NNPCa, n=61) and PCa (n=97). Growth-associated protein-43, nerve growth factor (NGF), and Artemin expressions were assessed by Immunohistochemistry, Western-Blot, and quantitative real time polymerase chain reaction-analyses. Isolated myenteric plexus of newborn rats were exposed to NP, NNPCa, and PCa tissue extracts and supernatants of Panc1 and T3M4 cancer cells with or without Artemin and NGF depletion, followed by neurite density analysis. Dense neural networks and enlarged nerves were not only detected in PCa but were also present in NNPCa. Growth-associated protein-43, NGF, and Artemin expressions were absent/weak in NP, but increased in both NNPCa and PCa and were closely associated with intrapancreatic neuropathy. PCa and NNPCa tissue extracts and Panc1/T3M4 supernatants noticeably increased neurite density in myenteric plexus-cultures, which were attenuated by depletion of NGF and Artemin. The neurotrophic effects of PCa extend into the peritumoral "normal" pancreatic areas without neuro-cancer interactions. The neurotrophic characteristics of PCa can be mimicked by in vitro analyses and reveal NGF and Artemin as potential key players in the generation of pancreatic neuropathy in PCa.

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Author and article information

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central

ISSN (Electronic): 1471-2407

Publication date Collection: 2013

Publication date (Electronic): 26 January 2013

Volume: 13

Page: 34

Affiliations

[1 ]Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China

[2 ]Department of Pathology, Anhui Medical University, Hefei, Anhui, People's Republic of China

[3 ]Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Centre for Life Sciences, #03-06C, 28 Medical Drive, Singapore, 117456, Singapore

[4 ]Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Anhui, Hefei, Anhui, People's Republic of China

[5 ]National Cancer Science Institute of Singapore, National University Health system, Singapore, Singapore

Article

Publisher ID: 1471-2407-13-34

DOI: 10.1186/1471-2407-13-34

PMC ID: 3562211

PubMed ID: 23351331

SO-VID: b34d4bb8-083d-4e6b-8f32-0d9269143749

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Prognostic significance of the expression of GFRα1, GFRα3 and Syndecan-3, proteins binding ARTEMIN, in mammary carcinoma

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Abstract

Background

Methods

Results

Conclusions

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Karger: Oncology

Most cited references 21

Prognostic significance of MMP-9 and TIMP-1 serum and tissue expression in breast cancer.

Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance.

Nerve growth factor and artemin are paracrine mediators of pancreatic neuropathy in pancreatic adenocarcinoma.

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