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BMC Cancer
Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

Induction of cell proliferation and survival genes by estradiol-repressed microRNAs in breast cancer cells

Authors: Xinfeng Yu, Xuemei Zhang, Ishwori B Dhakal, Marjorie Beggs, Susan Kadlubar, Dali Luo

Published in: BMC Cancer | Issue 1/2012

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Abstract

Background

In estrogen responsive MCF-7 cells, estradiol (E2) binding to ERα leads to transcriptional regulation of genes involved in the control of cell proliferation and survival. MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression. The aim of this study was to explore whether miRNAs were involved in hormonally regulated expression of estrogen responsive genes.

Methods

Western blot and QPCR were used to determine the expression of estrogen responsive genes and miRNAs respectively. Target gene expression regulated by miRNAs was validated by luciferase reporter assays and transfection of miRNA mimics or inhibitors. Cell proliferation was evaluated by MTS assay.

Results

E2 significantly induced bcl-2, cyclin D1 and survivin expression by suppressing the levels of a panel of miRNAs (miR-16, miR-143, miR-203) in MCF-7 cells. MiRNA transfection and luciferase assay confirmed that bcl-2 was regulated by miR-16 and miR-143, cyclinD1 was modulated by miR-16. Importantly, survivin was found to be targeted by miR-16, miR-143, miR-203. The regulatory effect of E2 can be either abrogated by anti-estrogen ICI 182, 780 and raloxifene pretreatment, or impaired by ERα siRNA, indicating the regulation is dependent on ERα. In order to investigate the functional significance of these miRNAs in estrogen responsive cells, miRNAs mimics were transfected into MCF-7 cells. It revealed that overexpression of these miRNAs significantly inhibited E2-induced cell proliferation. Further study of the expression of the miRNAs indicated that miR-16, miR-143 and miR-203 were highly expressed in triple positive breast cancer tissues, suggesting a potential tumor suppressing effect of these miRNAs in ER positive breast cancer.

Conclusions

These results demonstrate that E2 induces bcl-2, cyclin D1 and survivin by orchestrating the coordinate downregulation of a panel of miRNAs. In turn, the miRNAs manifest growth suppressive effects and control cell proliferation in response to E2. This sheds a new insight into the integral post-transcriptional regulation of cell proliferation and survival genes by miRNAs, a potential therapeutic option for breast cancer.
Appendix
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Literature
1.
2.
Ali S, Coombes RC: Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002, 2 (2): 101-112.CrossRefPubMed
3.
Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J, Brodsky AS, Keeton EK, Fertuck KC, Hall GF, et al: Genome-wide analysis of estrogen receptor binding sites. Nat Genet. 2006, 38 (11): 1289-1297.CrossRefPubMed
4.
Kushner PJ, Agard DA, Greene GL, Scanlan TS, Shiau AK, Uht RM, Webb P: Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol. 2000, 74 (5): 311-317.CrossRefPubMed
5.
Safe S: Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam Horm. 2001, 62: 231-252.CrossRefPubMed
6.
Shanmugam M, Krett NL, Maizels ET, Cutler RE, Peters CA, Smith LM, O'Brien ML, Park-Sarge OK, Rosen ST, Hunzicker-Dunn M: Regulation of protein kinase C delta by estrogen in the MCF-7 human breast cancer cell line. Mol Cell Endocrinol. 1999, 148 (1-2): 109-118.CrossRefPubMed
7.
Perillo B, Sasso A, Abbondanza C, Palumbo G: 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.CrossRefPubMedPubMedCentral
8.
Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V: Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer. 2007, 109 (9): 1721-1728.CrossRefPubMed
9.
Castro-Rivera E, Samudio I, Safe S: Estrogen regulation of cyclin D1 gene expression in ZR-75 breast cancer cells involves multiple enhancer elements. J Biol Chem. 2001, 276 (33): 30853-30861.CrossRefPubMed
10.
Sabbah M, Courilleau D, Mester J, Redeuilh G: Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proc Natl Acad Sci USA. 1999, 96 (20): 11217-11222.CrossRefPubMedPubMedCentral
11.
Cicatiello L, Addeo R, Sasso A, Altucci L, Petrizzi VB, Borgo R, Cancemi M, Caporali S, Caristi S, Scafoglio C, et al: Estrogens and progesterone promote persistent CCND1 gene activation during G1 by inducing transcriptional derepression via c-Jun/c-Fos/estrogen receptor (progesterone receptor) complex assembly to a distal regulatory element and recruitment of cyclin D1 to its own gene promoter. Mol Cell Biol. 2004, 24 (16): 7260-7274.CrossRefPubMedPubMedCentral
12.
Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS: Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology. 2003, 144 (10): 4562-4574.CrossRefPubMed
13.
McKenna NJ, O'Malley BW: Minireview: nuclear receptor coactivators-an update. Endocrinology. 2002, 143 (7): 2461-2465.PubMed
14.
Glass CK, Rosenfeld MG: The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 2000, 14 (2): 121-141.PubMed
15.
16.
Lai EC: Micro RNAs are complementary to 3' UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet. 2002, 30 (4): 363-364.CrossRefPubMed
17.
18.
Bhat-Nakshatri P, Wang G, Collins NR, Thomson MJ, Geistlinger TR, Carroll JS, Brown M, Hammond S, Srour EF, Liu Y, et al: Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic Acids Res. 2009, 37 (14): 4850-4861.CrossRefPubMedPubMedCentral
19.
Yamagata K, Fujiyama S, Ito S, Ueda T, Murata T, Naitou M, Takeyama K, Minami Y, O'Malley BW, Kato S: Maturation of microRNA is hormonally regulated by a nuclear receptor. Mol Cell. 2009, 36 (2): 340-347.CrossRefPubMed
20.
Maillot G, Lacroix-Triki M, Pierredon S, Gratadou L, Schmidt S, Benes V, Roche H, Dalenc F, Auboeuf D, Millevoi S, et al: Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. Cancer Res. 2009, 69 (21): 8332-8340.CrossRefPubMed
21.
Yu X, Dhakal IB, Beggs M, Edavana VK, Williams S, Zhang X, Mercer K, Ning B, Lang NP, Kadlubar FF, et al: Functional genetic variants in the 3'-untranslated region of sulfotransferase isoform 1A1 (SULT1A1) and their effect on enzymatic activity. Toxicol Sci. 2010, 118 (2): 391-403.CrossRefPubMedPubMedCentral
22.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001, 25 (4): 402-408.CrossRefPubMed
23.
Wang TT, Phang JM: Effects of estrogen on apoptotic pathways in human breast cancer cell line MCF-7. Cancer Res. 1995, 55 (12): 2487-2489.PubMed
24.
Dong L, Wang W, Wang F, Stoner M, Reed JC, Harigai M, Samudio I, Kladde MP, Vyhlidal C, Safe S: Mechanisms of transcriptional activation of bcl-2 gene expression by 17beta-estradiol in breast cancer cells. J Biol Chem. 1999, 274 (45): 32099-32107.CrossRefPubMed
25.
Planas-Silva MD, Donaher JL, Weinberg RA: Functional activity of ectopically expressed estrogen receptor is not sufficient for estrogen-mediated cyclin D1 expression. Cancer Res. 1999, 59 (19): 4788-4792.PubMed
26.
Wickramasinghe NS, Manavalan TT, Dougherty SM, Riggs KA, Li Y, Klinge CM: Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells. Nucleic Acids Res. 2009, 37 (8): 2584-2595.CrossRefPubMedPubMedCentral
27.
Castellano L, Giamas G, Jacob J, Coombes RC, Lucchesi W, Thiruchelvam P, Barton G, Jiao LR, Wait R, Waxman J, et al: The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response. Proc Natl Acad Sci USA. 2009, 106 (37): 15732-15737.CrossRefPubMedPubMedCentral
28.
Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, et al: miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 2005, 102 (39): 13944-13949.CrossRefPubMedPubMedCentral
29.
Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, Memeo L, D'Urso L, Pagliuca A, Biffoni M, Labbaye C, et al: The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med. 2008, 14 (11): 1271-1277.CrossRefPubMed
30.
Borralho PM, Kren BT, Castro RE, da Silva IB, Steer CJ, Rodrigues CM: MicroRNA-143 reduces viability and increases sensitivity to 5-fluorouracil in HCT116 human colorectal cancer cells. FEBS J. 2009, 276 (22): 6689-6700.CrossRefPubMed
31.
Robertson JF: Faslodex (ICI 182, 780), a novel estrogen receptor downregulator-future possibilities in breast cancer. J Steroid Biochem Mol Biol. 2001, 79 (1-5): 209-212.CrossRefPubMed
32.
Wakeling AE, Dukes M, Bowler J: A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991, 51 (15): 3867-3873.PubMed
33.
Fuchs-Young R, Glasebrook AL, Short LL, Draper MW, Rippy MK, Cole HW, Magee DE, Termine JD, Bryant HU: Raloxifene is a tissue-selective agonist/antagonist that functions through the estrogen receptor. Ann N Y Acad Sci. 1995, 761: 355-360.CrossRefPubMed
34.
35.
Esquela-Kerscher A, Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006, 6 (4): 259-269.CrossRefPubMed
36.
Fu M, Wang C, Li Z, Sakamaki T, Pestell RG: Minireview: Cyclin D1: normal and abnormal functions. Endocrinology. 2004, 145 (12): 5439-5447.CrossRefPubMed
37.
Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, Haines GK, Siegel PM, Hung MC, Yarden Y, et al: Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol. 2000, 20 (2): 672-683.CrossRefPubMedPubMedCentral
38.
Hockenbery DM: The bcl-2 oncogene and apoptosis. Semin Immunol. 1992, 4 (6): 413-420.PubMed
39.
Korsmeyer SJ: Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood. 1992, 80 (4): 879-886.PubMed
40.
Zhang R, Ma L, Zheng M, Ren J, Wang T, Meng Y, Zhao J, Jia L, Yao L, Han H, et al: Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice. Cancer Gene Ther. 2010, 17 (4): 275-288.CrossRefPubMed
41.
Altieri DC: Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene. 2003, 22 (53): 8581-8589.CrossRefPubMed
42.
Chen X, Guo X, Zhang H, Xiang Y, Chen J, Yin Y, Cai X, Wang K, Wang G, Ba Y, et al: Role of miR-143 targeting KRAS in colorectal tumorigenesis. Oncogene. 2009, 28 (10): 1385-1392.CrossRefPubMed
43.
Akao Y, Nakagawa Y, Naoe T: MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers. Oncol Rep. 2006, 16 (4): 845-850.PubMed
44.
Esau C, Kang X, Peralta E, Hanson E, Marcusson EG, Ravichandran LV, Sun Y, Koo S, Perera RJ, Jain R, et al: MicroRNA-143 regulates adipocyte differentiation. J Biol Chem. 2004, 279 (50): 52361-52365.CrossRefPubMed
45.
Borralho PM, Simoes AE, Gomes SE, Lima RT, Carvalho T, Ferreira DM, Vasconcelos MH, Castro RE, Rodrigues CM: miR-143 overexpression impairs growth of human colon carcinoma xenografts in mice with induction of apoptosis and inhibition of proliferation. PLoS One. 2011, 6 (8): e23787-CrossRefPubMedPubMedCentral
46.
Wang X, Tournier C: Regulation of cellular functions by the ERK5 signalling pathway. Cell Signal. 2006, 18 (6): 753-760.CrossRefPubMed
47.
Lupien M, Jeyakumar M, Hebert E, Hilmi K, Cotnoir-White D, Loch C, Auger A, Dayan G, Pinard GA, Wurtz JM, et al: Raloxifene and ICI182, 780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12. Mol Endocrinol. 2007, 21 (4): 797-816.CrossRefPubMed
48.
Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K: Modulation of microRNA processing by p53. Nature. 2009, 460 (7254): 529-533.CrossRefPubMed
49.
Liu W, Ip MM, Podgorsak MB, Das GM: Disruption of estrogen receptor alpha-p53 interaction in breast tumors: a novel mechanism underlying the anti-tumor effect of radiation therapy. Breast Cancer Res Treat. 2009, 115 (1): 43-50.CrossRefPubMed
50.
Menendez D, Inga A, Resnick MA: Estrogen receptor acting in cis enhances WT and mutant p53 transactivation at canonical and noncanonical p53 target sequences. Proc Natl Acad Sci USA. 2010, 107 (4): 1500-1505.CrossRefPubMedPubMedCentral
51.
Ofir M, Hacohen D, Ginsberg D: miR-15 and miR-16 Are direct transcriptional targets of E2F1 that limit E2F-induced proliferation by targeting cyclin E. Mol Cancer Res. 2011, 9 (4): 440-447.CrossRefPubMed
52.
Akao Y, Nakagawa Y, Hirata I, Iio A, Itoh T, Kojima K, Nakashima R, Kitade Y, Naoe T: Role of anti-oncomirs miR-143 and -145 in human colorectal tumors. Cancer Gene Ther. 2010, 17 (6): 398-408.CrossRefPubMed
53.
Xu B, Niu X, Zhang X, Tao J, Wu D, Wang Z, Li P, Zhang W, Wu H, Feng N, et al: miR-143 decreases prostate cancer cells proliferation and migration and enhances their sensitivity to docetaxel through suppression of KRAS. Mol Cell Biochem. 2011, 350 (12): 207-213.CrossRefPubMed
54.
Noguchi S, Mori T, Hoshino Y, Maruo K, Yamada N, Kitade Y, Naoe T, Akao Y: MicroRNA-143 functions as a tumor suppressor in human bladder cancer T24 cells. Cancer Lett. 2011, 307 (2): 211-220.CrossRefPubMed
55.
Viticchie G, Lena AM, Latina A, Formosa A, Gregersen LH, Lund AH, Bernardini S, Mauriello A, Miano R, Spagnoli LG, et al: MiR-203 controls proliferation, migration and invasive potential of prostate cancer cell lines. Cell Cycle. 2011, 10 (7): 1121-1131.CrossRefPubMed
56.
Saini S, Majid S, Yamamura S, Tabatabai ZL, Suh SO, Shahryari V, Chen Y, Deng G, Tanaka Y, Dahiya R: Regulatory role of miR-203 in prostate cancer progression and metastasis. Clin Cancer Res. 2011, 17 (16): 5287-5298.CrossRefPubMed
57.
Li J, Chen Y, Zhao J, Kong F, Zhang Y: miR-203 reverses chemoresistance in p53-mutated colon cancer cells through downregulation of Akt2 expression. Cancer Lett. 2011, 304 (1): 52-59.CrossRefPubMed
Metadata
Title
Induction of cell proliferation and survival genes by estradiol-repressed microRNAs in breast cancer cells
Authors
Xinfeng Yu
Xuemei Zhang
Ishwori B Dhakal
Marjorie Beggs
Susan Kadlubar
Dali Luo
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-29

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