Research Progress of uPAR in HER-2 Positive Breast Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Yang ¹ , ZHANG Xinyu ¹ , XU Guangmeng ² , WAN Guangwen ² , JIANG Fuquan ²

1.Department of Medical Oncology， General Hospital of Jilin Chemical Group Corporation， Jilin 132022， Jilin Province， China;;
2.Department of General Surgery， Second Hospital of Jilin University， Changchun 130000， Jilin Province， China;

Corresponding author：

Keywords：

Human epidermal growth factor receptor-2; Urokinase-type plasminogen activator receptor; RNA intervention

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Objective 　Investigate the effect and treatment prospects of urokinase-type plasminogen activator receptor（uPAR）in human epidermal growth factor receptor-2 （HER-2） positive breast cancer.
Method 　Aricals related effect of uPAR in HER-2 positive breast caner were retrieved through Pubmed， and the role of uPAR was reviewed.
Results 　uPAR played a very important role in the HER-2 positive breast cancer， anti-uPAR monomer or uPAR binding inhibitors could inhibit the growth， invasion and metastasis of breast cancer cells.
Conclusion 　uPAR is one of the effective target for breast cancer， and it provides a new breakthrough in the treatment of HER-2 positive breast cancer.

Citation： LIU Yang,ZHANG Xinyu,XU Guangmeng,WAN Guangwen,JIANG Fuquan. Research Progress of uPAR in HER-2 Positive Breast Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2012, 19(10): 1143-1146. doi: Copy

1.	Slamon DJ， Clark GM， Wong SG， et al. Human breast cancer：correlation of relapse and survival with amplification of the HER-2/neu oncogene[J]. Science， 1987， 235(4785)：177-182.
2.	Kanno Y， Matsuno H， Kawashita E， et al. Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue[J]. Thromb Haemost， 2010， 104(6)：1124-1132.
3.	Slamon DJ， Godolphin W， Jones LA， et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer[J]. Science，.
4.	Tsutsui S， Ohno S， Murakami S， et al. Prognostic value ofc-erbB2 expression in breast cancer[J]. Surg Oncol， 2002，79(4)：216-223.
5.	JU X， Katiyar S， Wang C，et al. Akt1 governs breast cancerprogression in vivo[J]. Proc Natl Acad Sci U S A， 2007，104(18)：7438-7443.
6.	Julien SG， Dubé N， Read M， et al. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammarytumorigenesis and protects from lung metastasis[J]. Nat Genet， 2007， 39(3)：338-346.
7.	Seton-Rogers SE， Lu Y， Hines LM， et al. Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells[J]. Proc Natl Acad Sci U S A， 2004， 101(5)： 1257-1262.
8.	Worzfeld T， Swiercz JM， Looso M， et al. ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis[J]. J Clin Invest， 2012， 122(4)： 1296-1305.
9.	Baselga J， Gelmon KA， Verma S， et al. PhaseⅡtrial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy[J]. J Clin Oncol， 2010，28(7)： 1138-44.
10.	Gianni L， Pienkowski T，Im YH，et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced， inflammatory， or early HER2-positive breast cancer（NeoSphere）：a randomised multicentre， open-label， phase 2 trial[J]. Lancet Oncol，2012， 13(1)：25-32.
11.	Bartsch R， Berghoff A， Pluschnig U， et al. Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases[J]. Br J Cancer， 2012， 106(1)：25-31.
12.	Maruyama T， Mimura K， Izawa S， et al. Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. [J]. Anticancer Res， 2011， 31(9)：2999-3005.
13.	Del Rosso M， Margheri F， Serratì S， et al. The urokinase receptor system， a key regulator at the intersection between inflammation， immunity， and coagulation.[J]. Curr Pharm Des， 2011， 17(19)：1924-1943.
14.	Sidenius N， Blasi F. The urokinase plasminogen activator system in cancer：recent advances and implication for prognosis and therapy[J]. Cancer Metastasis Rev，2003， 22(2-3)：205-222.
15.	Thummarati P， Wijitburaphat S， Prasopthum A， et al. High level of urokinase plasminogen activator contributes to cholangiocarcinoma invasion and metastasis[J]. World J Gastroenterol， 2012， 18(3)：244-250.
16.	XUE A， XUE M， Jackson C， et al. Suppression of urokinase plasminogen activator receptor inhibits proliferation and migration of pancreatic adenocarcinoma cells via regulation of ERK/p38 signaling[J]. Int J Biochem Cell Biol， 2009， 41(8-9)： 1731-1738.
17.	Provost JJ， Rastedt D， Canine J， et al. Urokinase plasminogen activator receptor induced non-small cell lung cancer invasion and metastasis requires NHE1 transporter expression and transport activity[J]. Cell Oncol（Dordr）， 2012，2(31)： 102-109.
18.	Nowicki TS， Zhao H， Darzynkiewicz Z， et al. Downregulation of uPAR inhibits migration， invasion， proliferation， FAK/PI3K/Akt signaling and induces senescence in papillary thyroid carcinoma cells[J]. Cell Cycle， 2011， 10(1)： 100-107.
19.	Nowicki TS， Kummer NT， Iacob C， et al. Inhibition of uPAR and uPA reduces invasion in papillary thyroid carcinoma cells[J]. Laryngoscope， 2010，120(7)： 1383-1390.
20.	Ahmad A， Kong D， Sarkar SH， et al. Inactivation of uPA and its receptor uPAR by 3，3’-diindolylmethane（DIM）leads to theinhibition of prostate cancer cell growth and migration[J]. J Cell Biochem， 2009， 107(3)：516-527.
21.	Mirmohammadsadegh A， Tartler U， Michel G， et al. HAX-1，identified by differential display reverse transcription polymerase chain reaction， is overexpressed in lesional psoriasis[J]. J InvestDermatol， 2003，120(6)： 1045-1051.
22.	Jiang Y， Zhang W， Kondo K， et al. Gene expression profiling in a renal cell carcinoma cell line：dissecting VHL and hypoxia-dependent pathways[J]. Mol Cancer Res， 2003， 1(6)： 453-462.
23.	Mekkawy AH， Morris DL， Pourgholami MH. HAX1 augments cell proliferation，migration，adhesion，and invasion induced by urokinase-type plasminogen activator receptor[J]. J Oncol， 2012， 4(3)：35-41.
24.	Blasi F， Carmeliet P. uPAR：a versatile signalling orchestrator[J]. Nat Rev Mol Cell Biol， 2002， 3(12)： 932-943.
25.	Pillay V， Crispin RD， Choong PM. The urokinase plasminogen activator receptor as a gene therapy target for cancer[J]. Trends Biotechnol， 2007， 25(1)： 33-39.
26.	Look MP， van Putten WL， Duffy MJ， et al. Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients[J]. J Natl Cancer Inst， 2002，94(2)：116-128.
27.	Andreasen PA， Kjøller L， Christensen L， et al. The urokinase-type plasminogen activator system in cancer metastasis：a review[J]. Int J Cancer， 1997， 72(1)：1-22.
28.	Tan M， Li P， Sun M， et al. Upregulation and activation of PKC alpha by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKC alpha and Src inhibitors[J]. Oncogene， 2006， 25(23)：3286-3295.
29.	Meng S， Tripathy D， Shete S， et al. uPAR and HER-2 genestatus in individual breast cancer cells from blood and tissues[J]. Proc Natl Acad Sci U S A， 2006， 103(46)：17361-17365.
30.	Mabrouk RA， Ali-Labib R. Detection of urokinase plasminogen activator receptor and c-erbB-2 in sera of patients with breast and ovarian carcinoma[J]. Clin Biochem， 2003， 36(7)： 537-543.
31.	Li C， Cao S， Liu Z，et al. RNAi-mediated downregulation of uPAR synergizes with targeting of HER2 through the ERK pathway in breast cancer cells[J]. Int J Cancer， 2010， 127(7)： 1507-1516.
32.	Kotzsch M， Bernt K， Friedrich K， et al. Prognostic relevance of tumour cell-associated uPAR expression in invasive ductal breast carcinoma[J]. Histopathology， 2010， 57(3)： 461-471.
33.	Ahmad A， Kong D， Wang Z， et al. Down-regulation of uPA and uPAR by 3，3’-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells[J]. J CellBiochem， 2009， 108(4)： 916-925.
34.	Berg D， Wolff C， Malinowsky K， et al. Profiling signalling pathways in formalin-fixed and paraffin-embedded breast cancer tissues reveals cross-talk between EGFR，HER2，HER3 and uPAR[J]. J Cell Physiol， 2012， 227(1)： 204-212.
35.	， 244(4905)： 707-712.

1. Slamon DJ， Clark GM， Wong SG， et al. Human breast cancer：correlation of relapse and survival with amplification of the HER-2/neu oncogene[J]. Science， 1987， 235(4785)：177-182.
2. Kanno Y， Matsuno H， Kawashita E， et al. Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue[J]. Thromb Haemost， 2010， 104(6)：1124-1132.
3. Slamon DJ， Godolphin W， Jones LA， et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer[J]. Science，.
4. Tsutsui S， Ohno S， Murakami S， et al. Prognostic value ofc-erbB2 expression in breast cancer[J]. Surg Oncol， 2002，79(4)：216-223.
5. JU X， Katiyar S， Wang C，et al. Akt1 governs breast cancerprogression in vivo[J]. Proc Natl Acad Sci U S A， 2007，104(18)：7438-7443.
6. Julien SG， Dubé N， Read M， et al. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammarytumorigenesis and protects from lung metastasis[J]. Nat Genet， 2007， 39(3)：338-346.
7. Seton-Rogers SE， Lu Y， Hines LM， et al. Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells[J]. Proc Natl Acad Sci U S A， 2004， 101(5)： 1257-1262.
8. Worzfeld T， Swiercz JM， Looso M， et al. ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis[J]. J Clin Invest， 2012， 122(4)： 1296-1305.
9. Baselga J， Gelmon KA， Verma S， et al. PhaseⅡtrial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy[J]. J Clin Oncol， 2010，28(7)： 1138-44.
10. Gianni L， Pienkowski T，Im YH，et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced， inflammatory， or early HER2-positive breast cancer（NeoSphere）：a randomised multicentre， open-label， phase 2 trial[J]. Lancet Oncol，2012， 13(1)：25-32.
11. Bartsch R， Berghoff A， Pluschnig U， et al. Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases[J]. Br J Cancer， 2012， 106(1)：25-31.
12. Maruyama T， Mimura K， Izawa S， et al. Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. [J]. Anticancer Res， 2011， 31(9)：2999-3005.
13. Del Rosso M， Margheri F， Serratì S， et al. The urokinase receptor system， a key regulator at the intersection between inflammation， immunity， and coagulation.[J]. Curr Pharm Des， 2011， 17(19)：1924-1943.
14. Sidenius N， Blasi F. The urokinase plasminogen activator system in cancer：recent advances and implication for prognosis and therapy[J]. Cancer Metastasis Rev，2003， 22(2-3)：205-222.
15. Thummarati P， Wijitburaphat S， Prasopthum A， et al. High level of urokinase plasminogen activator contributes to cholangiocarcinoma invasion and metastasis[J]. World J Gastroenterol， 2012， 18(3)：244-250.
16. XUE A， XUE M， Jackson C， et al. Suppression of urokinase plasminogen activator receptor inhibits proliferation and migration of pancreatic adenocarcinoma cells via regulation of ERK/p38 signaling[J]. Int J Biochem Cell Biol， 2009， 41(8-9)： 1731-1738.
17. Provost JJ， Rastedt D， Canine J， et al. Urokinase plasminogen activator receptor induced non-small cell lung cancer invasion and metastasis requires NHE1 transporter expression and transport activity[J]. Cell Oncol（Dordr）， 2012，2(31)： 102-109.
18. Nowicki TS， Zhao H， Darzynkiewicz Z， et al. Downregulation of uPAR inhibits migration， invasion， proliferation， FAK/PI3K/Akt signaling and induces senescence in papillary thyroid carcinoma cells[J]. Cell Cycle， 2011， 10(1)： 100-107.
19. Nowicki TS， Kummer NT， Iacob C， et al. Inhibition of uPAR and uPA reduces invasion in papillary thyroid carcinoma cells[J]. Laryngoscope， 2010，120(7)： 1383-1390.
20. Ahmad A， Kong D， Sarkar SH， et al. Inactivation of uPA and its receptor uPAR by 3，3’-diindolylmethane（DIM）leads to theinhibition of prostate cancer cell growth and migration[J]. J Cell Biochem， 2009， 107(3)：516-527.
21. Mirmohammadsadegh A， Tartler U， Michel G， et al. HAX-1，identified by differential display reverse transcription polymerase chain reaction， is overexpressed in lesional psoriasis[J]. J InvestDermatol， 2003，120(6)： 1045-1051.
22. Jiang Y， Zhang W， Kondo K， et al. Gene expression profiling in a renal cell carcinoma cell line：dissecting VHL and hypoxia-dependent pathways[J]. Mol Cancer Res， 2003， 1(6)： 453-462.
23. Mekkawy AH， Morris DL， Pourgholami MH. HAX1 augments cell proliferation，migration，adhesion，and invasion induced by urokinase-type plasminogen activator receptor[J]. J Oncol， 2012， 4(3)：35-41.
24. Blasi F， Carmeliet P. uPAR：a versatile signalling orchestrator[J]. Nat Rev Mol Cell Biol， 2002， 3(12)： 932-943.
25. Pillay V， Crispin RD， Choong PM. The urokinase plasminogen activator receptor as a gene therapy target for cancer[J]. Trends Biotechnol， 2007， 25(1)： 33-39.
26. Look MP， van Putten WL， Duffy MJ， et al. Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients[J]. J Natl Cancer Inst， 2002，94(2)：116-128.
27. Andreasen PA， Kjøller L， Christensen L， et al. The urokinase-type plasminogen activator system in cancer metastasis：a review[J]. Int J Cancer， 1997， 72(1)：1-22.
28. Tan M， Li P， Sun M， et al. Upregulation and activation of PKC alpha by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKC alpha and Src inhibitors[J]. Oncogene， 2006， 25(23)：3286-3295.
29. Meng S， Tripathy D， Shete S， et al. uPAR and HER-2 genestatus in individual breast cancer cells from blood and tissues[J]. Proc Natl Acad Sci U S A， 2006， 103(46)：17361-17365.
30. Mabrouk RA， Ali-Labib R. Detection of urokinase plasminogen activator receptor and c-erbB-2 in sera of patients with breast and ovarian carcinoma[J]. Clin Biochem， 2003， 36(7)： 537-543.
31. Li C， Cao S， Liu Z，et al. RNAi-mediated downregulation of uPAR synergizes with targeting of HER2 through the ERK pathway in breast cancer cells[J]. Int J Cancer， 2010， 127(7)： 1507-1516.
32. Kotzsch M， Bernt K， Friedrich K， et al. Prognostic relevance of tumour cell-associated uPAR expression in invasive ductal breast carcinoma[J]. Histopathology， 2010， 57(3)： 461-471.
33. Ahmad A， Kong D， Wang Z， et al. Down-regulation of uPA and uPAR by 3，3’-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells[J]. J CellBiochem， 2009， 108(4)： 916-925.
34. Berg D， Wolff C， Malinowsky K， et al. Profiling signalling pathways in formalin-fixed and paraffin-embedded breast cancer tissues reveals cross-talk between EGFR，HER2，HER3 and uPAR[J]. J Cell Physiol， 2012， 227(1)： 204-212.
35. ， 244(4905)： 707-712.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research Progress of uPAR in HER-2 Positive Breast Cancer

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