Expression and Clinical Significance of DLL4 and S100A4 in Different Molecular Subtypes of Breast Carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Qun ¹ , YU Minghua ² , WANG Geng ¹ , WANG Minghua. ¹

1. Department of Endocrine and Vascular Surgery， Taihe Hospital， Hubei University of Medicine， Shiyan 442000， Hubei Province， China;;
2. Institute of Basic Medicine， Hubei University of Medicine， Shiyan 442000， Hubei Province， China;

Corresponding author：

Keywords：

Delta-like ligand 4; S100 calcium binding protein A4; Breast carcinoma; Molecular subtype; Prognosis

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Objective 　To study the expressions of Delta-like ligand 4 （DLL4） and S100A4 in breast carcinoma of differect molecular subtypes and explore its clinical significance.
Methods 　The expressions of DLL4 and S100A4 in all molecular subtypes were tested by SP immunohistochemistry in 108 cases of breast carcinoma and 40 cases of paracancerous tissues from Taihe Hospital. The Luminal A， Lumianl B， HER-2 over-expression， and basal-like subtypes was 51， 26， 17， and 14 cases， respectively. Then the correlation of DLL4 and S100A4 expression with patients’ clinical and pathological features were analyzed.
Results 　The positive expression rates of DLL4 and S100A4 in breast carcinoma was 67.6%（73/108）and 62.0%（67/108）respectively， which were significantly higher than those in paracancerous tissues〔22.5%（9/40） and 45.0%（18/40）〕， P＜0.05. The positive expression rates of DLL4 and S100A4 in breast carcinoma tissues of HER-2 over-expression and basal-like subtypes were significantly higher than those in breast carcinoma tissues of Luminal A and Luminal B subtypes （P＜0.05）. The expressions of DLL4 and S100A4 in breast carcinoma tissues with lymph node metastasis and without lymph node metastasis were significantly different（P＜0.05）. There was positiver elationship between the expressions of DLL4 and S100A4 in breast carcinoma tissues（rs=0.217，P＜0.01）.
Conclusions 　DLL4 and S100A4 are highly expressed in breast carcinoma tissues of HER-2 over-expression and basal-like subtypes， and are all related with prognosis of breast carcinoma. These results suggest that they might be important factors in breast carcinogenesis and tumor development， metastasis. These proteins are indicators of metastasis and predictors for prognosis of breast carcinoma.

Citation： WANG Qun,YU Minghua,WANG Geng,WANG Minghua.. Expression and Clinical Significance of DLL4 and S100A4 in Different Molecular Subtypes of Breast Carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2012, 19(9): 957-961. doi: Copy

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13.	Li JL， Sainson RC， Shi W， et al. Delta-like 4 Notch ligand regulates tumor angiogenesis， improves tumor vascular function， and promotes tumor growth in vivo[J]. Cancer Res， 2007， 67 (23)： 11244-11253.
14.	Buchler P， Gazdhar A，Schubert M， et al. The Notch signaling pathway is related to neurovaseular progression of pancreaticcancer[J]. Ann Surg， 2005， 242(6)：791-801.
15.	Mullendore ME， Koorstra JB， Li YM， et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer[J]. Clin Cancer Res， 2009， 15(7)：2291-2301.
16.	Martinez JC， Muller MM，Turley H， et al. Nuclear and membrane expression of the angiogenesis regulator delta-like ligand 4 (DLL4) in normal and malignant human tissues[J]. Histopathology， 2009， 54(5)：598-606.
17.	Grigorian M， Lukanidin E. Activator of metastasis in cancer cells， Mst1/S100A4 protein binds to tumor suppressor protein p53[J]. Genetika， 2003， 39(7)： 900-908.
18.	Fernandez-Fernandez MR， Veprintsev DB， Fersht AR. Proteins of the s100 family regulate the oligomerization of p53 tumorsuppressor[J]. Proc Natl Acad Sci USA， 2005， 102(13)：4735-4740.
19.	Lee WY， Su WC， Lin PW， et al. Expression of S100A4 and Met： potential predictors for metastasis and survival in early-stage breast cancer[J]. Oncology， 2004， 66(6)：429-438.
20.	李欣，张丽杰，宋英. S100A4蛋白在乳腺癌组织的表达及临床意义[J]. 现代肿瘤医学， 2008，16(3)：359-361.
21.	Rudland PS， Platt Higgins A， Renshaw C， et al. Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer[J]. Cancer Res， 2000， 60(6)： 1595-1603.
22.	Ambartsumian N， Grigorian M， Lukanidin E. Genetically modified mouse models to study the role of metastasis-promoting S100A4 (mts1) protein in metastatic mammary cancer[J].J Dairy Res， 2005， 72 (S1)： 27-33.
23.	Schmidt-Hansen B， Ornas D， Grigorian M， et al. Extracellular S100A4 (mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity[J]. Oncogene， 2004， 23(32)： 5487-5495.
24.	鲁林源，艾开兴，黄新余，等. S100A4、VEGF的表达与胰腺癌预后的关系[J]. 肿瘤， 2008， 28(4)： 326-329.
25.	Semov A， Moreno MJ， Onichtchenko A， et al. Metastasis-associated protein S100A4 induces angiogenesis through interaction with AnnexinⅡand accelerated plasmin formation[J]. J Biol Chem， 2005， 280(21)： 20833-20841.

1. Carey LA， Perou CM， Livasy CA， et al. Race， breast cancer subtypes， and survival in the Carolina Breast Cancer Study[J]. JAMA， 2006， 295(21)：2492-2502.
2. Patel NS， Li JL， Generali D. et al. Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function[J]. Caner Res， 2005， 65(19)：8690-8697.
3. Wang YY， Ye ZY， Zhao ZS， et al. High-level expression of S100A4 correlates with lymph node metastasis and poor prognosis in patients with gastric cancer[J]. Ann Surg Oncol， 2010， 17(1)： 89-97.
4. Boye K， Maelandsmo GM. S100A4 and metastasis： a small actor playing many roles[J]. Am J pathol， 2010， 176(2)：528-535.
5. Singletary SE， Allred C， Ashley P， et al. Staging system for breast cancer：revisions for the 6th edition of the AJCC Cancer Staging Manual[J]. Surg Clin North Am， 2003， 83(4)：803-819.
6. Kopfstein L， Christofori G. Metastasis：cell-autonomous mechanisms versus contributions by the tumor microenviroment[J]. Cell Mol Life Sci， 2006，63(4)： 449-468.
7. Bergers G， Benjamin LE. Tumorigenesis and the angiogenic switch[J]. Nat Rev Cancer， 2003， 3(6)：401-410.
8. Joyce JA. Therapeutic targeting of the tumor microenvironment[J]. Cancer Cell， 2005， 7(6)：513-520.
9. Kerbel RS. Tumor angiogenesis[J]. N Engl J Med， 2008， 358(19)：2039-2049.
10. Thurston G， Noguera-Troise I， Yancopoulos GD. The delta paradox： DLL4 blockade leads to more tumour vessels but less tumour growth[J]. Nat Rev Cancer， 2007， 7(5)：327-331.
11. Bray SJ. Notch signaling：a simple pathway becomes complex[J]. Nat Rev Mol Cell Biol， 2006， 7(9)：678-689.
12. Benedito R， Trindade A， Hirashima M， et al. Loss of Notch signalling induced by DLL4 causes arterial calibre reduction by increasing endothelial cell response to angiogenic stimuli[J]. BMC Dev Biol， 2008， 8：117.
13. Li JL， Sainson RC， Shi W， et al. Delta-like 4 Notch ligand regulates tumor angiogenesis， improves tumor vascular function， and promotes tumor growth in vivo[J]. Cancer Res， 2007， 67 (23)： 11244-11253.
14. Buchler P， Gazdhar A，Schubert M， et al. The Notch signaling pathway is related to neurovaseular progression of pancreaticcancer[J]. Ann Surg， 2005， 242(6)：791-801.
15. Mullendore ME， Koorstra JB， Li YM， et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer[J]. Clin Cancer Res， 2009， 15(7)：2291-2301.
16. Martinez JC， Muller MM，Turley H， et al. Nuclear and membrane expression of the angiogenesis regulator delta-like ligand 4 (DLL4) in normal and malignant human tissues[J]. Histopathology， 2009， 54(5)：598-606.
17. Grigorian M， Lukanidin E. Activator of metastasis in cancer cells， Mst1/S100A4 protein binds to tumor suppressor protein p53[J]. Genetika， 2003， 39(7)： 900-908.
18. Fernandez-Fernandez MR， Veprintsev DB， Fersht AR. Proteins of the s100 family regulate the oligomerization of p53 tumorsuppressor[J]. Proc Natl Acad Sci USA， 2005， 102(13)：4735-4740.
19. Lee WY， Su WC， Lin PW， et al. Expression of S100A4 and Met： potential predictors for metastasis and survival in early-stage breast cancer[J]. Oncology， 2004， 66(6)：429-438.
20. 李欣，张丽杰，宋英. S100A4蛋白在乳腺癌组织的表达及临床意义[J]. 现代肿瘤医学， 2008，16(3)：359-361.
21. Rudland PS， Platt Higgins A， Renshaw C， et al. Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer[J]. Cancer Res， 2000， 60(6)： 1595-1603.
22. Ambartsumian N， Grigorian M， Lukanidin E. Genetically modified mouse models to study the role of metastasis-promoting S100A4 (mts1) protein in metastatic mammary cancer[J].J Dairy Res， 2005， 72 (S1)： 27-33.
23. Schmidt-Hansen B， Ornas D， Grigorian M， et al. Extracellular S100A4 (mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity[J]. Oncogene， 2004， 23(32)： 5487-5495.
24. 鲁林源，艾开兴，黄新余，等. S100A4、VEGF的表达与胰腺癌预后的关系[J]. 肿瘤， 2008， 28(4)： 326-329.
25. Semov A， Moreno MJ， Onichtchenko A， et al. Metastasis-associated protein S100A4 induces angiogenesis through interaction with AnnexinⅡand accelerated plasmin formation[J]. J Biol Chem， 2005， 280(21)： 20833-20841.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expression and Clinical Significance of DLL4 and S100A4 in Different Molecular Subtypes of Breast Carcinoma

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