Inhibition Effect of Caveolin-1 on Breast Cancer Cells Proliferation In Vitro and In Vivo and Its Mechanisms_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Xiaohui ¹ ,  LI Fei ¹ , LUO Bin ¹ , LIU Shuang ² , CUI Yeqing ² , SUN Haichen. ²

1. Department of General Surgery， Xuanwu Hospital， Capital Medical University， Beijing 100053， China;;
2. Surgical Laboratory， Xuanwu Hospital， Capital Medical University， Beijing 100053， China;

Corresponding author：

LI Fei, Email: feili36@ccmu.edu.cn

Keywords：

Caveolin-1; Colony formation; Vascular endothelial growth factor; Xenograft

Video：

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Objective 　To investigate the effect of caveolion-1 on the growth and proliferation in human breast
cancer MCF7 cell in vitro and in vivo and approach its mechanisms.
Methods 　The plasmid pCI-neo-cav-1 and its corres-ponding empty vector （pCI-neo） were transfected into MCF7 cell line. The expressions of caveolin-1 and vascular endoth-elial growth factor （VEGF） in transfectants were subsequently confirmed by Western blot analysis. A pair of monoclonal cell lines， MCF7/cav-1 and MCF7/vec， were chose for future studies. The colony formation ability of tumor cells was detected by anchorage-independent growth assay. Xenograft tumor models in nude mice were established. Immunohisto-chemistry was used to characterize Ki-67 and VEGF levels in the tumors tissues.
Results 　Caveolin-1 expression was up-regulated in the MCF7/cav-1 cell as compared with the MCF7/vec cell （P＜0.01） and the MCF7 cell （P＜0.01）. Caveolin-1 overexpression markedly reduced the capacity of the cells to form colonies in soft agar （P＜0.01）. Compared with the MCF7/vec cell， VEGF protein expression reduced in the MCF7/cav-1 cell （P＜0.01）. In vivo experiments in nude mice， the overexpression of caveolin-1 resulted in significant growth inhibition of the xenograft breast tumors. The Ki-67 staining was weak and the VEGF staining was negative by immunohistochemistry that indicated the caveolin-1 inhibited the proliferation in human breast cancer MCF7 cell.
Conclusion 　The caveolin-1 might inhibit the growth and proliferation in human breast cancer MCF7 cell through suppressing activation of VEGF signaling pathway.

Citation： WANG Xiaohui,LI Fei,LUO Bin,LIU Shuang,CUI Yeqing,SUN Haichen.. Inhibition Effect of Caveolin-1 on Breast Cancer Cells Proliferation In Vitro and In Vivo and Its Mechanisms. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2013, 20(5): 481-486. doi: Copy

1.	Jemal A， Bray F， Center MM， et al. Global cancer statistics[J].CA Cancer J Clin， 2011， 61(2)：69-90.
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13.	Witkiewicz AK， Dasgupta A， Sammons S， et al. Loss of stromalcaveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers[J]. Cancer Biol Ther， 2010， 10(2)：135-143.
14.	Chiu WT， Lee HT， Huang FJ， et al. Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition[J]. Cancer Res， 2011， 71(14)：4932-4943.
15.	Pancotti F， Roncuzzi L， Maggiolini M， et al. Caveolin-1 silencingarrests the proliferation of metastatic lung cancer cells through the inhibition of STAT3 signaling[J]. Cell Signal， 2012， 24(7)：1390-1397.
16.	Sato M， Hutchinson DS， Halls ML， et al. Interaction with caveolin-1modulates G protein coupling of mouse β3-adrenoceptor[J]. J Biol Chem， 2012， 287(24)：20674-20688.
17.	Arpaia E， Blaser H， Quintela-Fandino M， et al. The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src， Ras and Erk[J]. Oncogene， 2012， 31(7)：884-896.
18.	Tahir SA， Park S， Thompson TC. Caveolin-1 regulates VEGF-stimulated angiogenic activities in prostate cancer and endothelial cells[J]. Cancer Biol Ther， 2009， 8(23)：2286-2296.
19.	Li M， Chen H， Diao L， et al. Caveolin-1 and VEGF-C promote lymph node metastasis in the absence of intratumoral lymphangiogenesis in non-small cell lung cancer[J]. Tumori， 2010， 96(5)：734-743.
20.	Mehta RR， Yamada T， Taylor BN， et al. A cell penetrating peptidederived from azurin inhibits angiogenesis and tumor growth by inhibiting phosphorylation of VEGFR-2， FAK and Akt[J].Angiogenesis， 2011， 14(3)：355-369.
21.	Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis：a crucial target for anti- and pro-angiogenic therapies[J]. Genes Cancer， 2011， 2(12)：1097-1105.
22.	Salva E， Kabasakal L， Eren F， et al. Local delivery of chitosan/VEGF siRNA nanoplexes reduces angiogenesis and growth of breast cancer in vivo[J]. Nucleic acid therapeutics， 2012， 22(1)：40-48.
23.	Carroll CE， Liang Y， Benakanakere I， et al. The anticancer agent YC-1 suppresses progestin-stimulated VEGF in breast cancercells and arrests breast tumor development[J]. Int J Oncol， 2013， 42(1)：179-187.
24.	Belugali Nataraj N， Salimath BP. Crosstalk between VEGF and novel angiogenic protein regulates tumor angiogenesis and contri-butes to aggressiveness of breast carcinoma[J]. Cell Signal， 2013， 25(1)：277-294.
25.	Agelaki S， Spiliotaki M， Markomanolaki H， et al. Caveolin-1 regulates EGFR signaling in MCF-7 breast cancer cells and enha-nces gefitinib-induced tumor cell inhibition[J]. Cancer Biol Ther， 2009， 8(15)：1470-1477.

1. Jemal A， Bray F， Center MM， et al. Global cancer statistics[J].CA Cancer J Clin， 2011， 61(2)：69-90.
2. 陈万青，郑荣寿，曾红，等. 1989-2008年中国恶性肿瘤发病趋势分析[J]. 中华肿瘤杂志， 2012， 34(7)：517-524.
3. Quest AF， Gutierrez-Pajares JL， Torres VA. Caveolin-1：an ambiguous partner in cell signalling and cancer[J]. J Cell Mol Med， 2008， 12(4)：1130-1150.
4. Sáinz-Jaspeado M， Martin-Liberal J， Lagares-Tena L， et al. Caveolin-1 in sarcomas：friend or foe?[J]. Oncotarget， 2011， 2(4)：305-312.
5. Trimmer C， Whitaker-Menezes D， Bonuccelli G， et al. CAV1 inhibits metastatic potential in melanomas through suppression of the integrin/Src/FAK signaling pathway[J]. Cancer Res， 2010， 70(19)：7489-7499.
6. Sanna E， Miotti S， Mazzi M， et al. Binding of nuclear caveolin-1to promoter elements of growth-associated genes in ovarian carcinoma cells[J]. Exp Cell Res， 2007， 313(7)：1307-1317.
7. Prinetti A， Cao T， Illuzzi G， et al. A glycosphingolipid/caveolin-1signaling complex inhibits motility of human ovarian carcinoma cells[J]. J Biol Chem， 2011， 286(47)：40900-40910.
8. Murakami S， Miyamoto M， Hida Y， et al. Caveolin-1 overexpression is a favourable prognostic factor for patients with extrahepatic bile duct carcinoma[J]. Br J Cancer， 2003， 88(8)：1234-1238.
9. Gu D， Li H， Wang Z， et al. Caveolin-1 inhibits the growth of human laryngeal squamous cell carcinoma and down regulates EGFR-MAPKs signaling pathway[J]. Laryngoscope， 2007， 117(10)：1782-1789.
10. 王晓辉，李非，郑亚民，等. caveolin-1通过阻断PI3K/Akt信号的激活抑制胰腺癌细胞增殖[J]. 中国普外基础与临床杂志， 2011， 18(10)：1054-1059.
11. Cordes N， Frick S， Brunner TB， et al. Human pancreatic tumor cells are sensitized to ionizing radiation by knockdown of caveolin-1[J]. Oncogene， 2007， 26(48)：6851-6862.
12. Wu P， Qi B， Zhu H， et al. Suppression of staurosporine-mediatedapoptosis in Hs578T breast cells through inhibition of neutral-sphingomyelinase by caveolin-1[J]. Cancer Lett， 2007， 256(1)：64-72.
13. Witkiewicz AK， Dasgupta A， Sammons S， et al. Loss of stromalcaveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers[J]. Cancer Biol Ther， 2010， 10(2)：135-143.
14. Chiu WT， Lee HT， Huang FJ， et al. Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition[J]. Cancer Res， 2011， 71(14)：4932-4943.
15. Pancotti F， Roncuzzi L， Maggiolini M， et al. Caveolin-1 silencingarrests the proliferation of metastatic lung cancer cells through the inhibition of STAT3 signaling[J]. Cell Signal， 2012， 24(7)：1390-1397.
16. Sato M， Hutchinson DS， Halls ML， et al. Interaction with caveolin-1modulates G protein coupling of mouse β3-adrenoceptor[J]. J Biol Chem， 2012， 287(24)：20674-20688.
17. Arpaia E， Blaser H， Quintela-Fandino M， et al. The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src， Ras and Erk[J]. Oncogene， 2012， 31(7)：884-896.
18. Tahir SA， Park S， Thompson TC. Caveolin-1 regulates VEGF-stimulated angiogenic activities in prostate cancer and endothelial cells[J]. Cancer Biol Ther， 2009， 8(23)：2286-2296.
19. Li M， Chen H， Diao L， et al. Caveolin-1 and VEGF-C promote lymph node metastasis in the absence of intratumoral lymphangiogenesis in non-small cell lung cancer[J]. Tumori， 2010， 96(5)：734-743.
20. Mehta RR， Yamada T， Taylor BN， et al. A cell penetrating peptidederived from azurin inhibits angiogenesis and tumor growth by inhibiting phosphorylation of VEGFR-2， FAK and Akt[J].Angiogenesis， 2011， 14(3)：355-369.
21. Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis：a crucial target for anti- and pro-angiogenic therapies[J]. Genes Cancer， 2011， 2(12)：1097-1105.
22. Salva E， Kabasakal L， Eren F， et al. Local delivery of chitosan/VEGF siRNA nanoplexes reduces angiogenesis and growth of breast cancer in vivo[J]. Nucleic acid therapeutics， 2012， 22(1)：40-48.
23. Carroll CE， Liang Y， Benakanakere I， et al. The anticancer agent YC-1 suppresses progestin-stimulated VEGF in breast cancercells and arrests breast tumor development[J]. Int J Oncol， 2013， 42(1)：179-187.
24. Belugali Nataraj N， Salimath BP. Crosstalk between VEGF and novel angiogenic protein regulates tumor angiogenesis and contri-butes to aggressiveness of breast carcinoma[J]. Cell Signal， 2013， 25(1)：277-294.
25. Agelaki S， Spiliotaki M， Markomanolaki H， et al. Caveolin-1 regulates EGFR signaling in MCF-7 breast cancer cells and enha-nces gefitinib-induced tumor cell inhibition[J]. Cancer Biol Ther， 2009， 8(15)：1470-1477.

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