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Regulatory effects of ΔFosB on proliferation and apoptosis of MCF-7 breast cancer cells

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Tumor Biology

Abstract

Matrix metalloproteinase-9 (MMP-9) plays a vital role in tumor angiogenesis, cell migration, and invasiveness because it can degrade almost all basement membrane and extracellular matrix components. MMP-9 has been reported in many cancers including breast cancer, lung cancer, and colon cancer. ΔFosB in mammary epithelial cells has been shown to regulate cell proliferation, differentiation, and death. We found that ΔFosB increased the expression of MMP-9 in MCF-7 breast cancer cells. ΔFosB overexpression in MCF-7 cells increased cellular viability and decreased cell apoptosis. SB-3CT, an inhibitor of MMP-9, promoted apoptosis, inhibited cell proliferation, induced cell cycle arrest, and downregulated the expression of antiapoptotic genes Bcl-2 and Bcl-xl in MCF-7 cells. ΔFosB increased the number of MCF-7 cells in G2/M and S phases, upregulated the expression of Bcl-2 and Bcl-xl, and protected MCF-7 cells from apoptosis induced by MMP-9 inhibition. We also found that ΔFosB overexpression in MCF-7 cells inhibited Ca2+-induced apoptosis and promoted cell proliferation. Therefore, ΔFosB may be a potential target in breast cancer cell apoptosis by regulating the expression of MMP-9.

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References

  1. Shaulian E, Karin M. Ap-1 as a regulator of cell life and death. Nat Cell Biol. 2002;4:E131–6.

    Article  CAS  PubMed  Google Scholar 

  2. Shaulian E, Karin M. Ap-1 in cell proliferation and survival. Oncogene. 2001;20:2390–400.

    Article  CAS  PubMed  Google Scholar 

  3. Chu W-M. Tumor necrosis factor. Cancer Lett. 2013;328:222–5.

    Article  CAS  PubMed  Google Scholar 

  4. Sabatakos G, Sims N, Chen J, Aoki K, Kelz M, Amling M, et al. Overexpression of δfosb transcription factor(s) increases bone formation and inhibits adipogenesis. Nat Med. 2000;6:985–90.

    Article  CAS  PubMed  Google Scholar 

  5. Tahara K, Tsuchimoto D, Tominaga Y, Asoh S, Ohta S, Kitagawa M, et al. Δfosb, but not fosb, induces delayed apoptosis independent of cell proliferation in the rat1a embryo cell line. Cell Death Differ. 2003;10:496–507.

    Article  CAS  PubMed  Google Scholar 

  6. Miura T, Ohnishi Y, Kurushima H, Horie H, Kadoya T, Nakabeppu Y. Regulation of the neuronal fate by δfosb and its downstream target, galectin-1. Curr Drug Targets. 2005;6:437–44.

    Article  CAS  PubMed  Google Scholar 

  7. Smith LM, Wise SC, Hendricks DT, Sabichi AL, Bos T, Reddy P, et al. Cjun overexpression in mcf-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype. Oncogene. 1999;18:6063–70.

    Article  CAS  PubMed  Google Scholar 

  8. Kurushima H, Ohno M, Miura T, Nakamura T, Horie H, Kadoya T, et al. Selective induction of δfosb in the brain after transient forebrain ischemia accompanied by an increased expression of galectin-1, and the implication of δfosb and galectin-1 in neuroprotection and neurogenesis. Cell Death Differ. 2005;12:1078–96.

    Article  CAS  PubMed  Google Scholar 

  9. Kveiborg M, Sabatakos G, Chiusaroli R, Wu M, Philbrick WM, Horne WC, et al. Δfosb induces osteosclerosis and decreases adipogenesis by two independent cell-autonomous mechanisms. Mol Cell Biol. 2004;24:2820–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Daniele A, Zito A, Giannelli G, Divella R, Asselti M, Mazzocca A, et al. Expression of metalloproteinases mmp-2 and mmp-9 in sentinel lymph node and serum of patients with metastatic and non-metastatic breast cancer. Anticancer Res. 2010;30:3521–7.

    CAS  PubMed  Google Scholar 

  11. Bellafiore M, Battaglia G, Bianco A, Farina F, Palma A, Paoli A. The involvement of mmp-2 and mmp-9 in heart exercise-related angiogenesis. J Transl Med. 2013;11:283.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Merkle M, Ribeiro A, Sauter M, Ladurner R, Mussack T, Sitter T, et al. Effect of activation of viral receptors on the gelatinases mmp-2 and mmp-9 in human mesothelial cells. Matrix Biol. 2010;29:202–8.

    Article  CAS  PubMed  Google Scholar 

  13. Fernández CA, Yan L, Louis G, Yang J, Kutok JL, Moses MA. The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin Cancer Res. 2005;11:5390–5.

    Article  PubMed  Google Scholar 

  14. Cortes-Reynosa P, Robledo T, Macias-Silva M, Wu SV, Salazar EP. Src kinase regulates metalloproteinase-9 secretion induced by type iv collagen in mcf-7 human breast cancer cells. Matrix Biol. 2008;27:220–31.

    Article  CAS  PubMed  Google Scholar 

  15. Coussens LM, Tinkle CL, Hanahan D, Werb Z. Mmp-9 supplied by bone marrow–derived cells contributes to skin carcinogenesis. Cell. 2000;103:481–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2000;2:737–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Aalinkeel R, Nair MP, Sufrin G, Mahajan SD, Chadha KC, Chawda RP, et al. Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells. Cancer Res. 2004;64:5311–21.

    Article  CAS  PubMed  Google Scholar 

  18. Farina AR, Cappabianca L, DeSantis G, Di Ianni N, Ruggeri P, Ragone M, et al. Thioredoxin stimulates mmp-9 expression, de-regulates the mmp-9/timp-1 equilibrium and promotes mmp-9 dependent invasion in human mda-mb-231 breast cancer cells. FEBS Lett. 2011;585:3328–36.

    Article  CAS  PubMed  Google Scholar 

  19. Liacini A, Sylvester J, Li WQ, Zafarullah M. Inhibition of interleukin-1-stimulated map kinases, activating protein-1 (ap-1) and nuclear factor kappa b (nf-kappa b) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol. 2002;21:251–62.

    Article  CAS  PubMed  Google Scholar 

  20. Troussard AA, Costello P, Yoganathan TN, Kumagai S, Roskelley CD, Dedhar S. The integrin linked kinase (ilk) induces an invasive phenotype via ap-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (mmp-9). Oncogene. 2000;19:5444–52.

    Article  CAS  PubMed  Google Scholar 

  21. Lee S-O, Jeong Y-J, Im HG, Kim C-H, Chang Y-C, Lee I-S. Silibinin suppresses pma-induced mmp-9 expression by blocking the ap-1 activation via mapk signaling pathways in mcf-7 human breast carcinoma cells. Biochem Biophys Res Commun. 2007;354:165–71.

    Article  CAS  PubMed  Google Scholar 

  22. Kim S, Choi JH, Kim JB, Nam SJ, Yang J-H, Kim J-H, et al. Berberine suppresses tnf-α-induced mmp-9 and cell invasion through inhibition of ap-1 activity in mda-mb-231 human breast cancer cells. Molecules. 2008;13:2975–85.

    Article  CAS  PubMed  Google Scholar 

  23. Zheng H, Li H, Li L, Ma S, Liu X. Δfosb regulates Ca2+ release and proliferation of goat mammary epithelial cells. Gene. 2014;545:241–6.

    Article  CAS  PubMed  Google Scholar 

  24. Zhu J, Luo J, Sun Y, Shi H, Li J, Wu M, et al. Short communication: effect of inhibition of fatty acid synthase on triglyceride accumulation and effect on lipid metabolism genes in goat mammary epithelial cells. J Dairy Sci. 2015;98:3485–91.

    Article  CAS  PubMed  Google Scholar 

  25. Lin C-W, Hou W-C, Shen S-C, Juan S-H, Ko C-H, Wang L-M, et al. Quercetin inhibition of tumor invasion via suppressing pkcδ/erk/ap-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis. 2008;29:1807–15.

    Article  CAS  PubMed  Google Scholar 

  26. Li H, Zheng H, Sun Y, Yu Q, Li L. Signal transducer and activator of transcription 5a inhibited by pimozide may regulate survival of goat mammary gland epithelial cells by regulating parathyroid hormone-related protein. Gene. 2014;551:279–89.

    Article  CAS  PubMed  Google Scholar 

  27. Zhivotovsky B, Orrenius S. Calcium and cell death mechanisms: a perspective from the cell death community. Cell Calcium. 2011;50:211–21.

    Article  CAS  PubMed  Google Scholar 

  28. Crowe DL, Brown TN. Transcriptional inhibition of matrix metal loproteinase 9 (mmp-9) activity by a c-fos/estrogen receptor fusion protein is mediated by the proximal ap-1 site of the mmp-9 promoter and correlates with reduced tumor cell invasion. Neoplasia. 1999;1:368–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pratap J, Wixted JJ, Gaur T, Zaidi SK, Dobson J, Gokul KD, et al. Runx2 transcriptional activation of Indian hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res. 2008;68:7795–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Leifler KS, Svensson S, Abrahamsson A, Bendrik C, Robertson J, Gauldie J, et al. Inflammation induced by mmp-9 enhances tumor regression of experimental breast cancer. J Immunol. 2013;190:4420–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen HB, Gao WW, Yang Y, Guo SY, Wang H, Wang W, et al. Inhibition of vdac1 prevents Ca2+-mediated oxidative stress and apoptosis induced by 5-aminolevulinic acid mediated sonodynamic therapy in thp-1 macrophages. Apoptosis. 2014;19:1712–26.

    Article  CAS  PubMed  Google Scholar 

  32. Lam M, Dubyak G, Chen L, Nunez G, Miesfeld RL, Distelhorst CW. Evidence that bcl-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. Proc Natl Acad Sci. 1994;91:6569–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rong Y, Distelhorst CW. Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Annu Rev Physiol. 2008;70:73–91.

    Article  CAS  PubMed  Google Scholar 

  34. Greenberg EF, Lavik AR, Distelhorst CW. Bcl-2 regulation of the inositol 1, 4, 5-trisphosphate receptor and calcium signaling in normal and malignant lymphocytes: potential new target for cancer treatment. Biochim Biophys Acta (BBA)-Mol Cell Res. 2014;1843:2205–10.

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by the “National Natural Science Foundation of China (No. 31572368)” and “Special Fund for Agro-scientific Research in the Public Interest (No.201103038)”.

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    Authors and Affiliations

    1. Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, No. 22 Xinong Road, Yangling, Shaanxi, 712100, China

      Hui Li, Lihui Li, Huiling Zheng, Xiaotong Yao & Wenjuan Zang

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    1. Hui Li
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    2. Lihui Li
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    Correspondence to Huiling Zheng.

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    Hui Li and Lihui Li contributed equally to this work.

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    Fig. S1

    ΔFosB increases MMP-9 expression in cultured MCF-7 breast cancer cells. The MCF-7 cells were transduced with ΔFosB interference recombinant adenoviruses Ad-ΔFosB-572 for 24 h and subsequently were transduced with overexpression recombinant adenoviruses Ad-ΔFosB for 48 h. MMP-9 mRNA levels were analyzed by quantitative real-time PCR (RT-qPCR). Values are means ± SEM (n = 3). *P<0.05; **P<0.01; *** P<0.001. Ad-ΔFosB the overexpression recombinant adenoviruses of ΔFosB, Ad-ΔFosB-572 the interference recombinant adenoviruses of ΔFosB. (GIF 21 kb)

    High Resolution (TIF 102 kb)

    Fig. S2

    ΔFosB-dependent protection from SB-3CT-induced cell apoptosis in MCF-7 breast cancer cells. MCF-7 cells were transduced with Ad-ΔFosB or Ad-ΔFosB-572 for 48 h and subsequently exposed to different concentrations of SB-3CT for 24 h. Cell apoptosis was determined by Annexin V-FITC/PI binding followed by flow cytometry. Values are means ± SEM (n = 3). *P<0.05; **P<0.01; *** P<0.001. Ad-ΔFosB the overexpression recombinant adenoviruses of ΔFosB, Ad-ΔFosB-572 the interference recombinant adenoviruses of ΔFosB, SB-3CT an inhibitor of MMP-9. (GIF 45 kb)

    High Resolution (TIF 197 kb)

    Fig. S3

    ΔFosB-dependent protection from Ca2+-induced cell apoptosis in MCF-7 breast cancer cells. MCF-7 cells were transduced with Ad-ΔFosB or Ad-ΔFosB-572 for 48 h, and subsequently exposed to different concentrations of Ca2+ for 24 h. Cell apoptosis was determined Annexin V-FITC/PI binding followed by flow cytometry. Values are means ± SEM (n = 3). *P<0.05; **P<0.01; *** P<0.001. Ad-ΔFosB the overexpression recombinant adenoviruses of ΔFosB, Ad-ΔFosB-572 the interference recombinant adenoviruses of ΔFosB. (GIF 49 kb)

    High Resolution (TIF 541 kb)

    Fig. S4

    The effects of Ca2+ on the mRNA expression of ΔFosB and MMP-9. MCF-7 cells were treated with different concentrations of Ca2+ for 24 h, and the mRNA levels of ΔFosB and MMP-9 were analyzed by quantitative real-time PCR (RT-qPCR). Values are means ± SEM (n = 3). *P<0.05; **P<0.01; *** P<0.001. (GIF 15 kb)

    High Resolution (TIF 65 kb)

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    Li, H., Li, L., Zheng, H. et al. Regulatory effects of ΔFosB on proliferation and apoptosis of MCF-7 breast cancer cells. Tumor Biol. 37, 6053–6063 (2016). https://doi.org/10.1007/s13277-015-4356-4

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    • DOI: https://doi.org/10.1007/s13277-015-4356-4

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