Expression of Mdm2 in ERα-Positive Breast Cancer Tissue and Its Biologic Effect on MCF-7 Cells_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 SHIYun , WANGGeng , ZHOUKun ,  LIWen-fang

Department of Breast Cancer Surgery, Taihe Hospital Affiliated to Hubei Medical University, Shiyan 442000, Hubei Province, China;

Corresponding author：

LIWen-fang, Email: 2671422764@qq.com

Keywords：

Mdm2; Estrogen receptor α; Breast cancer; MCF-7 cells

DOI：

10.7507/1007-9424.20160275

Video：

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Objective To explore expression of Mdm2 in the estrogen receptor α (ERα)-positive breast cancer tissues and fibroadenoma of breast tissues, and to explore the effect of MDM2-siRNA on cell proliferation, colony formation, and apoptosis for MCF-7 cells. Methods ① Seventy eight ERα-positive breast cancer patients identified by histopathological examination, who underwent surgery in our hospital from June 2012 to October 2015, as well as 10 fibroadenoma of breast patients underwent surgery in the same period, were collected retrospectively to determine the expression of Mdm2, then explore the relationship between the expression of Mdm2 and clinical pathological characteristics of ERα-positive breast cancer patients. ② MCF-7 cells were divided to MDM2-siRNA group (added with MDM2-siRNA), negative control group (added with negative siRNA), and blank control group (added without any reagent). Expression of Mdm2, cell proliferation rate, number of colony formation, and apoptosis rate were determined in the MCF-7 cells of 3 groups. Results ① No one of fibroadenoma of breast patients was found positive expression of Mdm2 (0/10), and 38 of 78 ERα-positive breast cancer patients were found the positive expression of Mdm2 (48.7%), which is higher than that of fibroadenoma of breast tissues (χ²=12.357, P=0.000). In ERα-positive breast cancer patients, expression of Mdm2 was related with TNM staging and number of metastasic lymph node (P < 0.050), the positive expression rate of Mdm2 was higher in patients with later TNM staging or more metastasic lymph node. ② Cell proliferation rates on 2, 3, and 4 days after transfection, expression level of Mdm2, and number of colony formation were all lower (P < 0.050), but the apoptosis rate was higher in MDM2-siRNA group (P < 0.050), comparing with negative control group and blank control group. But there was no significant difference between negative control group and blank control group on aforementioned indexes (P > 0.050). Conclusion Mdm2 is a diagnostic marker in ERα-positive breast cancer patients, and treatment targeting it might has a certain therapeutic value.

Citation： SHI Yun, WANG Geng, ZHOU Kun, LI Wen-fang. Expression of Mdm2 in ERα-Positive Breast Cancer Tissue and Its Biologic Effect on MCF-7 Cells. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2016, 23(9): 1066-1072. doi: 10.7507/1007-9424.20160275 Copy

1.	Perillo B, Sasso A, Abbondanza C, et al. 17beta-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Mol Cell Biol, 2000, 20(8):2890-2901.
2.	Wu X, Zahari MS, Renuse S, et al. Phosphoproteomic analysis identifies focal adhesion kinase 2(FAK2) as a potential therapeutic target for tamoxifen resistance in breast cancer. Mol Cell Proteomics, 2015, 14(11):2887-2900.
3.	Ma G, Pan Y, Zhou C, et al. Mitogen-activated protein kinase phosphatase 1 is involved in tamoxifen resistance in MCF7 cells. Oncol Rep, 2015, 34(5):2423-2430.
4.	Liu HC, Ma F, Shen Y, et al. Overexpression of SMAR1 enhances radiosensitivity in human breast cancer cell line MCF7 via activation of p53 signaling pathway. Oncol Res, 2014, 22(5):293-300.
5.	Qin JJ, Wang W, Voruganti S, et al. Identification of a new class of natural product MDM2 inhibitor:in vitro and in vivo anti-breast cancer activities and target validation. Oncotarget, 2015, 6(5):2623-2640.
6.	Berger CE, Qian Y, Liu G, et al. p53, a target of estrogen receptor (ER)α, modulates DNA damage-induced growth suppression in ER-positive breast cancer cells. J Biol Chem, 2012, 287(36):30117-30127.
7.	Huang K, Tang Y, He L, et al. MicroRNA-340 inhibits prostate cancer cell proliferation and metastasis by targeting the MDM2-p53 pathway. Oncol Rep, 2016, 35(2):887-895.
8.	East EG, Pang JC, Kidwell KM, et al. Utility of estrogen receptor, progesterone receptor, and HER-2/neu analysis of multiple foci in multifocal ipsilateral invasive breast carcinoma. Am J Clin Pathol, 2015, 144(6):952-959.
9.	Mairinger FD, Walter RF, Ting S, et al. Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma. Future Oncol, 2014, 10(6):995-1005.
10.	Cahilly-Snyder L, Yang-Feng T, Francke U, et al. Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Somet Cell Mol Genet, 1987, 13(1):235-244.
11.	Deben C, Deschoolmeester V, Lardon F, et al. TP53 and MDM2 genetic alterations in non-small cell lung cancer:evaluating their prognostic and predictive value. Crit Rev Oncol Hematol, 2016, 99:63-73.
12.	Li H, Liu Q, Wang Z, et al. The oncoprotein HBXIP modulates the feedback loop of MDM2/p53 to enhance the growth of breast cancer. J Biol Chem, 2015, 290(37):22649-22661.
13.	Li Q, Zhang Y, El-Naggar AK, et al. Therapeutic efficacy of p53 restoration in Mdm2-overexpressing tumors. Mol Cancer Res, 2014, 12(6):901-911.
14.	Bhattacharya S, Ghosh MK. HAUSP, a novel deubiquitinase for Rb MDM2 the critical regulator. FEBS J, 2014, 281(13):3061-3078.
15.	Han S, Woo JK, Jung Y, et al. Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway. Biochem Biophys Res Commun, 2016, 469(4):1153-1158.
16.	Qin JJ, Wang W, Sarkar S, et al. Oral delivery of anti-MDM2 inhibitor SP141-loaded FcRn-targeted nanoparticles to treat breast cancer and metastasis. J Control Release, 2016, 237:101-114.
17.	Pellegrino M, Mancini F, Lucà R, et al. Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy. Cancer Res, 2015, 75(21):4560-4572.
18.	Jin Y, Lee H, Zeng SX, et al. MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. EMBO J, 2003, 22(23):6365-6377.
19.	Joshi S, Singh AR, Durden DL. MDM2 regulates hypoxic hypoxia-inducible factor 1α stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner. J Biol Chem, 2014, 289(33):22785-22797.
20.	Rice S, Pellat L, Ahmetaga A, et al. Dual effect of metformin on growth inhibition and oestradiol production in breast cancer cells. Int J Mol Med, 2015, 35(4):1088-1094.
21.	Chen Z, Wang Y, Warden C, et al. Cross-talk between ER and HER2 regulates c-MYC-mediated glutamine metabolism in aromatase inhibitor resistant breast cancer cells. J Steroid Biochem Mol Biol, 2015, 149:118-127.
22.	Larsen SL, Yde CW, Laenkholm AV, et al. Aurora kinase B is important for antiestrogen resistant cell growth and a potential biomarker for tamoxifen resistant breast cancer. BMC Cancer, 2015, 15:239.
23.	Wei C, Cao Y, Yang X, et al. Elevated expression of TANK-binding kinase 1 enhances tamoxifen resistance in breast cancer. Proc Natl Acad Sci U S A, 2014, 111(5):E601-E610.
24.	Dolfi SC, Jäger AV, Medina DJ, et al. Fulvestrant treatment alters MDM2 protein turnover and sensitivity of human breast carcinoma cells to chemotherapeutic drugs. Cancer Lett, 2014, 350(1-2):52-60.
25.	Kim K, Burghardt R, Barhoumi R, et al. MDM2 regulates estrogen receptor α and estrogen responsiveness in breast cancer cells. J Mol Endocrinol, 2011, 46(2):67-79.
26.	Brekman A, Singh KE, Polotskaia A, et al. A p53-independent role of Mdm2 in estrogen-mediated activation of breast cancer cell proliferation. Breast Cancer Res, 2011, 13(1):R3.

1. Perillo B, Sasso A, Abbondanza C, et al. 17beta-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Mol Cell Biol, 2000, 20(8):2890-2901.
2. Wu X, Zahari MS, Renuse S, et al. Phosphoproteomic analysis identifies focal adhesion kinase 2(FAK2) as a potential therapeutic target for tamoxifen resistance in breast cancer. Mol Cell Proteomics, 2015, 14(11):2887-2900.
3. Ma G, Pan Y, Zhou C, et al. Mitogen-activated protein kinase phosphatase 1 is involved in tamoxifen resistance in MCF7 cells. Oncol Rep, 2015, 34(5):2423-2430.
4. Liu HC, Ma F, Shen Y, et al. Overexpression of SMAR1 enhances radiosensitivity in human breast cancer cell line MCF7 via activation of p53 signaling pathway. Oncol Res, 2014, 22(5):293-300.
5. Qin JJ, Wang W, Voruganti S, et al. Identification of a new class of natural product MDM2 inhibitor:in vitro and in vivo anti-breast cancer activities and target validation. Oncotarget, 2015, 6(5):2623-2640.
6. Berger CE, Qian Y, Liu G, et al. p53, a target of estrogen receptor (ER)α, modulates DNA damage-induced growth suppression in ER-positive breast cancer cells. J Biol Chem, 2012, 287(36):30117-30127.
7. Huang K, Tang Y, He L, et al. MicroRNA-340 inhibits prostate cancer cell proliferation and metastasis by targeting the MDM2-p53 pathway. Oncol Rep, 2016, 35(2):887-895.
8. East EG, Pang JC, Kidwell KM, et al. Utility of estrogen receptor, progesterone receptor, and HER-2/neu analysis of multiple foci in multifocal ipsilateral invasive breast carcinoma. Am J Clin Pathol, 2015, 144(6):952-959.
9. Mairinger FD, Walter RF, Ting S, et al. Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma. Future Oncol, 2014, 10(6):995-1005.
10. Cahilly-Snyder L, Yang-Feng T, Francke U, et al. Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Somet Cell Mol Genet, 1987, 13(1):235-244.
11. Deben C, Deschoolmeester V, Lardon F, et al. TP53 and MDM2 genetic alterations in non-small cell lung cancer:evaluating their prognostic and predictive value. Crit Rev Oncol Hematol, 2016, 99:63-73.
12. Li H, Liu Q, Wang Z, et al. The oncoprotein HBXIP modulates the feedback loop of MDM2/p53 to enhance the growth of breast cancer. J Biol Chem, 2015, 290(37):22649-22661.
13. Li Q, Zhang Y, El-Naggar AK, et al. Therapeutic efficacy of p53 restoration in Mdm2-overexpressing tumors. Mol Cancer Res, 2014, 12(6):901-911.
14. Bhattacharya S, Ghosh MK. HAUSP, a novel deubiquitinase for Rb MDM2 the critical regulator. FEBS J, 2014, 281(13):3061-3078.
15. Han S, Woo JK, Jung Y, et al. Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway. Biochem Biophys Res Commun, 2016, 469(4):1153-1158.
16. Qin JJ, Wang W, Sarkar S, et al. Oral delivery of anti-MDM2 inhibitor SP141-loaded FcRn-targeted nanoparticles to treat breast cancer and metastasis. J Control Release, 2016, 237:101-114.
17. Pellegrino M, Mancini F, Lucà R, et al. Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy. Cancer Res, 2015, 75(21):4560-4572.
18. Jin Y, Lee H, Zeng SX, et al. MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. EMBO J, 2003, 22(23):6365-6377.
19. Joshi S, Singh AR, Durden DL. MDM2 regulates hypoxic hypoxia-inducible factor 1α stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner. J Biol Chem, 2014, 289(33):22785-22797.
20. Rice S, Pellat L, Ahmetaga A, et al. Dual effect of metformin on growth inhibition and oestradiol production in breast cancer cells. Int J Mol Med, 2015, 35(4):1088-1094.
21. Chen Z, Wang Y, Warden C, et al. Cross-talk between ER and HER2 regulates c-MYC-mediated glutamine metabolism in aromatase inhibitor resistant breast cancer cells. J Steroid Biochem Mol Biol, 2015, 149:118-127.
22. Larsen SL, Yde CW, Laenkholm AV, et al. Aurora kinase B is important for antiestrogen resistant cell growth and a potential biomarker for tamoxifen resistant breast cancer. BMC Cancer, 2015, 15:239.
23. Wei C, Cao Y, Yang X, et al. Elevated expression of TANK-binding kinase 1 enhances tamoxifen resistance in breast cancer. Proc Natl Acad Sci U S A, 2014, 111(5):E601-E610.
24. Dolfi SC, Jäger AV, Medina DJ, et al. Fulvestrant treatment alters MDM2 protein turnover and sensitivity of human breast carcinoma cells to chemotherapeutic drugs. Cancer Lett, 2014, 350(1-2):52-60.
25. Kim K, Burghardt R, Barhoumi R, et al. MDM2 regulates estrogen receptor α and estrogen responsiveness in breast cancer cells. J Mol Endocrinol, 2011, 46(2):67-79.
26. Brekman A, Singh KE, Polotskaia A, et al. A p53-independent role of Mdm2 in estrogen-mediated activation of breast cancer cell proliferation. Breast Cancer Res, 2011, 13(1):R3.

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Expression of Mdm2 in ERα-Positive Breast Cancer Tissue and Its Biologic Effect on MCF-7 Cells

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