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Interplay of nuclear receptors (ER, PR, and GR) and their steroid hormones in MCF-7 cells

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Abstract

Steroid hormones and their nuclear receptors play a major role in the development and progression of breast cancer. MCF-7 cells are triple-positive breast cancer cells expressing estrogen receptor (ER), progesterone receptor (PR), and glucocorticoid receptor (GR). However, interaction and their role in expression pattern of activator protein (AP-1) transcription factors (TFs) are not completely understood. Hence, in our study, MCF-7 cells were used as an in vitro model system to study the interplay between the receptors and hormones. MCF-7 cells were treated with estradiol-17β (E2), progesterone (P4), and dexamethasone (Dex), alone or in combination, to study the proliferation of cells and expression of AP-1 genes. MTT assay results show that E2 or P4 induced the cell proliferation by more than 35 %, and Dex decreased the proliferation by 26 %. E2 and P4 are found to increase ERα by more than twofold and c-Jun, c-Fos, and Fra-1 AP-1 TFs by more than 1.7-fold, while Dex shows opposite effect of E2- or P4-induced effect as well as effect on the expression of nuclear receptors and AP-1 factors. E2 antagonist Fulvestrant (ICI 182,780) found to reduce proliferation and E2-induced expression of AP1-TFs, while P4 or Dex antagonist Mifepristone (RU486) is found to block GR-mediated expression of NRs and AP-1 mRNAs. Results suggest that E2 and P4 act synergistically, and Dex acts as an antagonist of E2 and P4.

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References

  1. Brisken C, O’Malley B (2010) Hormone action in the mammary gland. Cold Spring Harb Perspect Biol 2:a003178. doi:10.1101/cshperspect.a003178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Humphreys RC, Lydon J, O’Malley BW, Rosen JM (1997) Mammary gland development is mediated by both stromal and epithelial progesterone receptors. Mol Endocrinol 11:801–811. doi:10.1210/mend.11.6.9891

    Article  CAS  PubMed  Google Scholar 

  3. Contrò V, Basile JR, Proia P (2015) Sex steroid hormone receptors, their ligands, and nuclear and non-nuclear pathways. AIMS Mol Sci 2:294–310. doi:10.3934/molsci.2015.3.294

    Article  Google Scholar 

  4. Simoncini T, Genazzani AR (2003) Non-genomic actions of sex steroid hormones. Eur J Endocrinol 148:281–292

    Article  CAS  PubMed  Google Scholar 

  5. Clarke CL, Sutherland RL (1990) Progestin regulation of cellular proliferation. Endocr Rev 11:266–301. doi:10.1210/edrv-11-2-266

    Article  CAS  PubMed  Google Scholar 

  6. Vesely PW, Staber PB, Hoefler G, Kenner L (2009) Translational regulation mechanisms of AP-1 proteins. Mutat Res 682:7–12. doi:10.1016/j.mrrev.2009.01.001

    Article  CAS  PubMed  Google Scholar 

  7. Bjornstrom L, Sjoberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19:833–842. doi:10.1210/me.2004-0486

    Article  PubMed  Google Scholar 

  8. Karmakar S, Jin Y, Nagaich AK (2013) Interaction of glucocorticoid receptor (GR) with estrogen receptor (ER) alpha and activator protein 1 (AP1) in dexamethasone-mediated interference of ERalpha activity. J Biol Chem 288:24020–24034. doi:10.1074/jbc.M113.473819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Uht RM, Anderson CM, Webb P, Kushner PJ (1997) Transcriptional activities of estrogen and glucocorticoid receptors are functionally integrated at the AP-1 response element. Endocrinology 138:2900–2908. doi:10.1210/endo.138.7.5244

    CAS  PubMed  Google Scholar 

  10. Leo JC, Guo C, Woon CT, Aw SE, Lin VC (2004) Glucocorticoid and mineralocorticoid cross-talk with progesterone receptor to induce focal adhesion and growth inhibition in breast cancer cells. Endocrinology 145:1314–1321. doi:10.1210/en.2003-0732

    Article  CAS  PubMed  Google Scholar 

  11. Wakeling AE, Bowler J (1987) Steroidal pure antioestrogens. J Endocrinol 112:R7–R10

    Article  CAS  PubMed  Google Scholar 

  12. Osborne CK, Wakeling A, Nicholson RI (2004) Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer 90(Suppl 1):S2–S6. doi:10.1038/sj.bjc.6601629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sharma SC, Purohit P, Rao AJ (1993) Role of oestradiol-17β in the regulation of synthesis and secretion of human chorionic gonadotrophin by first trimester human placenta. J Mol Endocrinol 11:91–101

    Article  CAS  PubMed  Google Scholar 

  14. Babu RL, Naveen Kumar M, Patil RH, Devaraju KS, Ramesh GT, Sharma SC (2013) Effect of estrogen and tamoxifen on the expression pattern of AP-1 factors in MCF-7 cells: role of c-Jun, c-Fos, and Fra-1 in cell cycle regulation. Mol Cell Biochem 380:143–151. doi:10.1007/s11010-013-1667-x

    Article  CAS  PubMed  Google Scholar 

  15. Patil RH, Babu RL, Naveen Kumar M, Kiran Kumar KM, Hegde SM, Ramesh GT, Chidananda Sharma S (2015) Apigenin inhibits PMA-induced expression of pro-inflammatory cytokines and AP-1 factors in A549 cells. Mol Cell Biochem 403:95–106. doi:10.1007/s11010-015-2340-3

    Article  CAS  PubMed  Google Scholar 

  16. Periyakaruppan A, Kumar F, Sarkar S, Sharma CS, Ramesh GT (2007) Uranium induces oxidative stress in lung epithelial cells. Arch Toxicol 81:389–395. doi:10.1007/s00204-006-0167-0

    Article  CAS  PubMed  Google Scholar 

  17. Sharma SC, Clemens JW, Pisarska MD, Richards JS (1999) Expression and function of estrogen receptor subtypes in granulosa cells: regulation by estradiol and forskolin. Endocrinology 140:4320–4334. doi:10.1210/endo.140.9.6965

    CAS  PubMed  Google Scholar 

  18. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  19. Cunha GR, Hom YK (1996) Role of mesenchymal-epithelial interactions in mammary gland development. J Mammary Gland Biol Neoplasia 1:21–35

    Article  CAS  PubMed  Google Scholar 

  20. Tan H, Zhong Y, Pan Z (2009) Autocrine regulation of cell proliferation by estrogen receptor-alpha in estrogen receptor-alpha-positive breast cancer cell lines. BMC Cancer 9:31. doi:10.1186/1471-2407-9-31

    Article  PubMed  PubMed Central  Google Scholar 

  21. Buxant F, Engohan-Aloghe C, Noel JC (2010) Estrogen receptor, progesterone receptor, and glucocorticoid receptor expression in normal breast tissue, breast in situ carcinoma, and invasive breast cancer. Appl Immunohistochem Mol Morphol 18:254–257. doi:10.1097/PAI.0b013e3181c10180

    Article  CAS  PubMed  Google Scholar 

  22. Pan D, Kocherginsky M, Conzen SD (2011) Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer Res 71:6360–6370. doi:10.1158/0008-5472.can-11-0362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bolt MJ, Stossi F, Newberg JY, Orjalo A, Johansson HE, Mancini MA (2013) Coactivators enable glucocorticoid receptor recruitment to fine-tune estrogen receptor transcriptional responses. Nucleic Acids Res 41:4036–4048. doi:10.1093/nar/gkt100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Guo CM, Zhu XO, Ni XT, Yang Z, Myatt L, Sun K (2009) Expression of progesterone receptor A form and its role in the interaction of progesterone with cortisol on cyclooxygenase-2 expression in amnionic fibroblasts. J Clin Endocrinol Metab 94:5085–5092. doi:10.1210/jc.2009-0832

    Article  CAS  PubMed  Google Scholar 

  25. Ponta H, Cato AC, Herrlich P (1992) Interference of pathway specific transcription factors. Biochim Biophys Acta 1129:255–261

    Article  CAS  PubMed  Google Scholar 

  26. Ross-Innes CS, Stark R, Holmes KA, Schmidt D, Spyrou C, Russell R, Massie CE, Vowler SL, Eldridge M, Carroll JS (2010) Cooperative interaction between retinoic acid receptor-alpha and estrogen receptor in breast cancer. Genes Dev 24:171–182. doi:10.1101/gad.552910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hua S, Kittler R, White KP (2009) Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell 137:1259–1271. doi:10.1016/j.cell.2009.04.043

    Article  PubMed  PubMed Central  Google Scholar 

  28. Need EF, Selth LA, Trotta AP, Leach DA, Giorgio L, O’Loughlin MA, Smith E, Gill PG, Ingman WV, Graham JD, Buchanan G (2015) The unique transcriptional response produced by concurrent estrogen and progesterone treatment in breast cancer cells results in upregulation of growth factor pathways and switching from a Luminal A to a Basal-like subtype. BMC Cancer 15:791. doi:10.1186/s12885-015-1819-3

    Article  PubMed  PubMed Central  Google Scholar 

  29. Buxant F, Kindt N, Laurent G, Noel JC, Saussez S (2015) Antiproliferative effect of dexamethasone in the MCF-7 breast cancer cell line. Mol Med Rep 12:4051–4054. doi:10.3892/mmr.2015.3920

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhou F, Bouillard B, Pharaboz-Joly MO, Andre J (1989) Non-classical antiestrogenic actions of dexamethasone in variant MCF-7 human breast cancer cells in culture. Mol Cell Endocrinol 66:189–197

    Article  CAS  PubMed  Google Scholar 

  31. Krishnan AV, Swami S, Feldman D (2001) Estradiol inhibits glucocorticoid receptor expression and induces glucocorticoid resistance in MCF-7 human breast cancer cells. J Steroid Biochem Mol Biol 77:29–37

    Article  CAS  PubMed  Google Scholar 

  32. Gong H, Jarzynka MJ, Cole TJ, Lee JH, Wada T, Zhang B, Gao J, Song WC, DeFranco DB, Cheng SY, Xie W (2008) Glucocorticoids antagonize estrogens by glucocorticoid receptor-mediated activation of estrogen sulfotransferase. Cancer Res 68:7386–7393. doi:10.1158/0008-5472.can-08-1545

    Article  CAS  PubMed  Google Scholar 

  33. Gundisch S, Boeckeler E, Behrends U, Amtmann E, Ehrhardt H, Jeremias I (2012) Glucocorticoids augment survival and proliferation of tumor cells. Anticancer Res 32:4251–4261

    CAS  PubMed  Google Scholar 

  34. Cui X, Schiff R, Arpino G, Osborne CK, Lee AV (2005) Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. J Clin Oncol 23:7721–7735. doi:10.1200/jco.2005.09.004

    Article  CAS  PubMed  Google Scholar 

  35. Fisher B, Wickerham DL, Brown A, Redmond CK (1983) Breast cancer estrogen and progesterone receptor values: their distribution, degree of concordance, and relation to number of positive axillary nodes. J Clin Oncol 1:349–358

    CAS  PubMed  Google Scholar 

  36. Horwitz KB, Mockus MB, Lessey BA (1982) Variant T47D human breast cancer cells with high progesterone-receptor levels despite estrogen and antiestrogen resistance. Cell 28:633–642

    Article  CAS  PubMed  Google Scholar 

  37. Daniel AR, Gaviglio AL, Knutson TP, Ostrander JH, D’Assoro AB, Ravindranathan P, Peng Y, Raj GV, Yee D, Lange CA (2015) Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes. Oncogene 34:506–515. doi:10.1038/onc.2013.579

    Article  CAS  PubMed  Google Scholar 

  38. Daniel AR, Gaviglio AL, Knutson TP, Ostrander JH, Yee D, Lange CA (2013) Unliganded progesterone receptors augment estrogen-induced growth of breast cancer cells via co-regulation of estrogen receptor target genes. Cancer Res 73:3572–3578

    Article  Google Scholar 

  39. Amsterdam A, Tajima K, Sasson R (2002) Cell-specific regulation of apoptosis by glucocorticoids: implication to their anti-inflammatory action. Biochem Pharmacol 64:843–850

    Article  CAS  PubMed  Google Scholar 

  40. Lippman M, Bolan G, Huff K (1976) The effects of glucocorticoids and progesterone on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 36:4602–4609

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors wish to express their gratitude to the Department of Science and Technology-Promotion of University Research and Scientific Excellence (DST-PURSE) [SR/59/Z-23/2010/38(c)] and University Grant Commission Centre with Potential for Excellence in Particular Area (UGC-CPEPA) [8-2/2008(NS/PE)], New Delhi for providing financial support. The authors also wish to express their gratitude to the Department of Microbiology and Biotechnology, Bangalore University, Bengaluru for providing the DST-FIST, UGC-SAP, and department facility.

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Authors and Affiliations

  1. Department of Microbiology and Biotechnology, Bangalore University, Jnana Bharathi, Bengaluru, Karnataka, 560 056, India

    Shubha M. Hegde, M. Naveen Kumar, K. Kavya, K. M. Kiran Kumar, Rashmi Nagesh, Rajeshwari H. Patil & S. Chidananda Sharma

  2. Department of Bioinformatics and Biotechnology, Karnataka State Women’s University, Jnanashakthi Campus, Vijayapura, Karnataka, 586 108, India

    R. L. Babu

  3. Department of Biology and Center for Biotechnology and Biomedical Sciences, Norfolk State University, Norfolk, VA, USA

    Govindarajan T. Ramesh

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  1. Shubha M. Hegde
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Correspondence to S. Chidananda Sharma.

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Hegde, S.M., Kumar, M.N., Kavya, K. et al. Interplay of nuclear receptors (ER, PR, and GR) and their steroid hormones in MCF-7 cells. Mol Cell Biochem 422, 109–120 (2016). https://doi.org/10.1007/s11010-016-2810-2

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