Survivin Regulation by HER2 Through NF-κB and C-myc in Irradiated Breast Cancer Cells

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2010 Aug 19

PMID 20716114

Citations 21

Authors

Vassilis Papanikolaou

Dimitrios Iliopoulos

Ioannis Dimou

Stephanie Dubos

Constantine Kappas

Sofia Kitsiou-Tzeli

Aspasia Tsezou

Affiliations

Soon will be listed here.

Abstract

Radiotherapy is an important treatment modality against cancer resulting in apoptosis and inhibition of cell growth. Survivin is an important cancer biomarker conferring to tumour cells increased survival potential by inhibiting apoptosis. In the present study, we investigated the implication of breast cancer cells features, as hormone receptors and p53 status, in the radio-resistance of breast cancer cells and in the regulation of survivin's expression by nuclear factor (NF)-κB and c-myc. Six breast cancer cell lines Michigan Cancer Foundation (MCF-7), MCF-7/Human Epidermal Growth Factor Receptor (HER)2, M. D. Anderson - Metastatic Breast (MDA-MB-231), SK-BR-3, BT-474 and Human Breast Lactating (HBL-100) were irradiated and cell viability as well as cell cycle distribution were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. Survivin mRNA and protein levels were evaluated by real time PCR and Western blot analysis. Survivin and HER2 gene knockdown was performed with siRNA technology and investigation of transcription factors binding to survivin and c-myc gene promoters was assessed by chromatin immunoprecipitation. Student's t-test and F-statistics were used for statistical evaluation. Our results demonstrated that only HER2(+) breast cancer cells up-regulated survivin upon irradiation, whereas HER2 knockdown in HER2(+) cells led to survivin's down-regulation. Survivin and especially HER2 knockdown abolished the observed G2/M cell cycle checkpoint and reduced the radio-resistance of HER2 overexpressing breast cancer cells. Additionally, HER2 was found to regulate survivin's expression through NF-κB and c-myc transcription factors. This study revealed the significance of HER2 in the radio-resistance of HER2(+) breast cancer cells through induction of transcription factors NF-κB and c-myc, leading to activation of survivin, a downstream target oncogene preventing apoptosis.

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References

Tamm I, Wang Y, Sausville E, Scudiero D, Vigna N, Oltersdorf T . IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res. 1998; 58(23):5315-20. View

Mita A, Mita M, Nawrocki S, Giles F . Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 2008; 14(16):5000-5. DOI: 10.1158/1078-0432.CCR-08-0746. View

Rodel F, Hoffmann J, Distel L, Herrmann M, Noisternig T, Papadopoulos T . Survivin as a radioresistance factor, and prognostic and therapeutic target for radiotherapy in rectal cancer. Cancer Res. 2005; 65(11):4881-7. DOI: 10.1158/0008-5472.CAN-04-3028. View

Martin D, Munoz R, Subler M, Deb S . p53 binds to the TATA-binding protein-TATA complex. J Biol Chem. 1993; 268(18):13062-7. View

Asanuma H, Torigoe T, Kamiguchi K, Hirohashi Y, Ohmura T, Hirata K . Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signaling pathway in breast cancer cells. Cancer Res. 2005; 65(23):11018-25. DOI: 10.1158/0008-5472.CAN-05-0491. View

Ma H, Nguyen C, Lee K, Kahn M . Differential roles for the coactivators CBP and p300 on TCF/beta-catenin-mediated survivin gene expression. Oncogene. 2005; 24(22):3619-31. DOI: 10.1038/sj.onc.1208433. View

Martinato F, Cesaroni M, Amati B, Guccione E . Analysis of Myc-induced histone modifications on target chromatin. PLoS One. 2008; 3(11):e3650. PMC: 2574517. DOI: 10.1371/journal.pone.0003650. View

Cuddihy A, Bristow R . The p53 protein family and radiation sensitivity: Yes or no?. Cancer Metastasis Rev. 2004; 23(3-4):237-57. DOI: 10.1023/B:CANC.0000031764.81141.e4. View

Li Q, Zhao J, Liu J, Jia L, Huang H, Xu Y . Survivin stable knockdown by siRNA inhibits tumor cell growth and angiogenesis in breast and cervical cancers. Cancer Biol Ther. 2006; 5(7):860-6. DOI: 10.4161/cbt.5.7.2893. View

10.

Ambrosini G, Adida C, Altieri D . A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997; 3(8):917-21. DOI: 10.1038/nm0897-917. View

11.

Gudkov A, Komarova E . The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer. 2003; 3(2):117-29. DOI: 10.1038/nrc992. View

12.

Sethi G, Ahn K, Aggarwal B . Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. Mol Cancer Res. 2008; 6(6):1059-70. DOI: 10.1158/1541-7786.MCR-07-2088. View

13.

Papanikolaou V, Iliopoulos D, Dimou I, Dubos S, Tsougos I, Theodorou K . The involvement of HER2 and p53 status in the regulation of telomerase in irradiated breast cancer cells. Int J Oncol. 2009; 35(5):1141-9. DOI: 10.3892/ijo_00000430. View

14.

Jiang Y, Saavedra H, Holloway M, Leone G, Altura R . Aberrant regulation of survivin by the RB/E2F family of proteins. J Biol Chem. 2004; 279(39):40511-20. DOI: 10.1074/jbc.M404496200. View

15.

Tanaka K, Iwamoto S, Gon G, Nohara T, Iwamoto M, Tanigawa N . Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res. 2000; 6(1):127-34. View

16.

Saito T, Hama S, Izumi H, Yamasaki F, Kajiwara Y, Matsuura S . Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells. Br J Cancer. 2008; 98(2):345-55. PMC: 2361434. DOI: 10.1038/sj.bjc.6604160. View

17.

Kanda N, Seno H, Konda Y, Marusawa H, Kanai M, Nakajima T . STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene. 2004; 23(28):4921-9. DOI: 10.1038/sj.onc.1207606. View

18.

Slamon D, Godolphin W, Jones L, Holt J, Wong S, Keith D . Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989; 244(4905):707-12. DOI: 10.1126/science.2470152. View

19.

Xia W, Bisi J, Strum J, Liu L, Carrick K, Graham K . Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res. 2006; 66(3):1640-7. DOI: 10.1158/0008-5472.CAN-05-2000. View

20.

Cosgrave N, Hill A, Young L . Growth factor-dependent regulation of survivin by c-myc in human breast cancer. J Mol Endocrinol. 2006; 37(3):377-90. DOI: 10.1677/jme.1.02118. View