Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 6/2011

Open Access 01-12-2011 | Research article

miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells

Authors: Yee-Ming Lee, Jen-Yi Lee, Chao-Chi Ho, Qi-Sheng Hong, Sung-Liang Yu, Chii-Ruey Tzeng, Pan-Chyr Yang, Huei-Wen Chen

Published in: Breast Cancer Research | Issue 6/2011

Login to get access

Abstract

Introduction

Estrogen is involved in several physiological and pathological processes through estrogen receptor (ER)-mediated transcriptional gene regulation. miRNAs (miRs), which are noncoding RNA genes, may respond to estrogen and serve as posttranscriptional regulators in tumorigenic progression, especially in breast cancer; however, only limited information about this possibility is available. In the present study, we identified the estrogen-regulated miR-34b and investigated its functional role in breast cancer progression.

Methods

Estrogen-regulated miRNAs were identified by using a TaqMan low density array. Our in vivo Tet-On system orthotopic model revealed the tumor-suppressive ability of miR-34b. Luciferase reporter assays and chromatin immunoprecipitation assay demonstrated miR-34b were regulated by p53-ER interaction.

Results

In this study, we identified one such estrogen downregulated miRNA, miR-34b, as an oncosuppressor that targets cyclin D1 and Jagged-1 (JAG1) in an ER+/wild-type p53 breast cancer cell line (MCF-7), as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ERα and miR-34b expression levels in ER+ breast cancer patients. Tet-On induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER+ breast tumor growth in an orthotopic mammary fat pad xenograft mouse model. Further validation indicated that estrogen's inhibition of miR-34b expression was mediated by interactions between ERα and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of the miR-34b targets cyclin D1 and JAG1 in MCF-7 cells.

Conclusions

These findings reveal that miR-34b is an oncosuppressor miRNA requiring both ER+ and wild-type p53 phenotypes in breast cancer cells. These results improve our ability to develop new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through miRNA regulation.
Appendix
Available only for authorised users
Literature
1.
Johnston SR: New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res. 2010, 16: 1979-1987. 10.1158/1078-0432.CCR-09-1823.CrossRefPubMed
2.
Ohshiro K, Kumar R: Evolving pathway-driven biomarkers in breast cancer. Expert Opin Investig Drugs. 2010, 19 (Suppl 1): S51-S56.CrossRefPubMed
3.
Alvarez RH, Valero V, Hortobagyi GN: Emerging targeted therapies for breast cancer. J Clin Oncol. 2010, 28: 3366-3379. 10.1200/JCO.2009.25.4011.CrossRefPubMed
4.
Rakha EA, Reis-Filho JS, Ellis IO: Combinatorial biomarker expression in breast cancer. Breast Cancer Res Treat. 2010, 120: 293-308. 10.1007/s10549-010-0746-x.CrossRefPubMed
5.
Ali S, Coombes RC: Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002, 2: 101-112. 10.1038/nrc721.CrossRefPubMed
6.
Zwart W, Theodorou V, Carroll JS: Estrogen receptor-positive breast cancer: a multidisciplinary challenge. Wiley Interdiscip Rev Syst Biol Med. 2011, 3: 216-230. 10.1002/wsbm.109.CrossRefPubMed
7.
Rana A, Rangasamy V, Mishra R: How estrogen fuels breast cancer. Future Oncol. 2010, 6: 1369-1371. 10.2217/fon.10.112.CrossRefPubMed
8.
Björnström L, Sjöberg M: Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol. 2005, 19: 833-842. 10.1210/me.2004-0486.CrossRefPubMed
9.
Marino M, Galluzzo P, Ascenzi P: Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics. 2006, 7: 497-508. 10.2174/138920206779315737.CrossRefPubMedPubMedCentral
10.
Green KA, Carroll JS: Oestrogen-receptor-mediated transcription and the influence of co-factors and chromatin state. Nat Rev Cancer. 2007, 7: 713-722. 10.1038/nrc2211.CrossRefPubMed
11.
Meister G, Tuschl T: Mechanisms of gene silencing by double-stranded RNA. Nature. 2004, 431: 343-349. 10.1038/nature02873.CrossRefPubMed
12.
Esquela-Kerscher A, Slack FJ: Oncomirs: microRNAs with a role in cancer. Nat Rev Cancer. 2006, 6: 259-269. 10.1038/nrc1840.CrossRefPubMed
13.
14.
Verghese ET, Hanby AM, Speirs V, Hughes TA: Small is beautiful: microRNAs and breast cancer: where are we now?. J Pathol. 2008, 215: 214-221. 10.1002/path.2359.CrossRefPubMed
15.
He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL, Linsley PS, Chen C, Lowe SW, Cleary MA, Hannon GJ: A microRNA component of the p53 tumour suppressor network. Nature. 2007, 447: 1130-1134. 10.1038/nature05939.CrossRefPubMedPubMedCentral
16.
Corney DC, Flesken-Nikitin A, Godwin AK, Wang W, Nikitin AY: MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Res. 2007, 67: 8433-8438. 10.1158/0008-5472.CAN-07-1585.CrossRefPubMed
17.
He L, He X, Lowe SW, Hannon GJ: microRNAs join the p53 network: another piece in the tumour-suppression puzzle. Nat Rev Cancer. 2007, 7: 819-822. 10.1038/nrc2232.CrossRefPubMedPubMedCentral
18.
Toyota M, Suzuki H, Sasaki Y, Maruyama R, Imai K, Shinomura Y, Tokino T: Epigenetic silencing of MicroRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. Cancer Res. 2008, 68: 4123-4132. 10.1158/0008-5472.CAN-08-0325.CrossRefPubMed
19.
Li LC, Dahiya R: MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002, 18: 1427-1431. 10.1093/bioinformatics/18.11.1427.CrossRefPubMed
20.
Das PM, Ramachandran K, vanWert J, Singal R: Chromatin immunoprecipitation assay. Biotechniques. 2004, 37: 961-969.PubMed
21.
González L, Agulló-Ortuño MT, García-Martínez JM, Calcabrini A, Gamallo C, Palacios J, Aranda A, Martín-Pérez J: Role of c-Src in human MCF7 breast cancer cell tumorigenesis. J Biol Chem. 2006, 281: 20851-20864. 10.1074/jbc.M601570200.CrossRefPubMed
22.
Golubovskaya VM, Zheng M, Zhang L, Li JL, Cance WG: The direct effect of focal adhesion kinase (FAK), dominant-negative FAK, FAK-CD and FAK siRNA on gene expression and human MCF-7 breast cancer cell tumorigenesis. BMC Cancer. 2009, 9: 280-10.1186/1471-2407-9-280.CrossRefPubMedPubMedCentral
23.
He X, He L, Hannon GJ: The guardian's little helper: microRNAs in the p53 tumor suppressor network. Cancer Res. 2007, 67: 11099-11101. 10.1158/0008-5472.CAN-07-2672.CrossRefPubMed
24.
Ji Q, Hao X, Meng Y, Zhang M, Desano J, Fan D, Xu L: Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer. 2008, 8: 266-10.1186/1471-2407-8-266.CrossRefPubMedPubMedCentral
25.
Rokhlin OW, Scheinker VS, Taghiyev AF, Bumcrot D, Glover RA, Cohen MB: MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer. Cancer Biol Ther. 2008, 7: 1288-1296. 10.4161/cbt.7.8.6284.CrossRefPubMed
26.
Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CK, Musgrove EA, Sutherland RL: Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993, 8: 2127-2133.PubMed
27.
Reedijk M, Odorcic S, Chang L, Zhang H, Miller N, McCready DR, Lockwood G, Egan SE: High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res. 2005, 65: 8530-8537. 10.1158/0008-5472.CAN-05-1069.CrossRefPubMed
28.
Cohen B, Shimizu M, Izrailit J, Ng NF, Buchman Y, Pan JG, Dering J, Reedijk M: Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer. Breast Cancer Res Treat. 2009, 123: 113-124.CrossRefPubMed
29.
Liu W, Ip MM, Podgorsak MB, Das GM: Disruption of estrogen receptor α-p53 interaction in breast tumors: a novel mechanism underlying the anti-tumor effect of radiation therapy. Breast Cancer Res Treat. 2009, 115: 43-50. 10.1007/s10549-008-0044-z.CrossRefPubMed
30.
Sayeed A, Konduri SD, Liu W, Bansal S, Li F, Das GM: Estrogen receptor α inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. Cancer Res. 2007, 67: 7746-7755. 10.1158/0008-5472.CAN-06-3724.CrossRefPubMed
31.
Liu W, Konduri SD, Bansal S, Nayak BK, Rajasekaran SA, Karuppayil SM, Rajasekaran AK, Das GM: Estrogen receptor-α binds p53 tumor suppressor protein directly and represses its function. J Biol Chem. 2006, 281: 9837-9840. 10.1074/jbc.C600001200.CrossRefPubMed
32.
Li S, Hursting SD, Davis BJ, McLachlan JA, Barrett JC: Environmental exposure, DNA methylation, and gene regulation: lessons from diethylstilbesterol-induced cancers. Ann N Y Acad Sci. 2003, 983: 161-169. 10.1111/j.1749-6632.2003.tb05971.x.CrossRefPubMed
33.
Götz F, Thieme S, Dörner G: Female infertility: effect of perinatal xenoestrogen exposure on reproductive functions in animals and humans. Folia Histochem Cytobiol. 2001, 39 (Suppl 2): 40-43.PubMed
34.
Liu S, Lin YC: Transformation of MCF-10A human breast epithelial cells by zeranol and estradiol-17β. Breast J. 2004, 10: 514-521. 10.1111/j.1075-122X.2004.21410.x.CrossRefPubMed
35.
Quick EL, Parry EM, Parry JM: Do oestrogens induce chromosome specific aneuploidy in vitro, similar to the pattern of aneuploidy seen in breast cancer?. Mutat Res. 2008, 651: 46-55.CrossRefPubMed
36.
Carey L, Winer E, Viale G, Cameron D, Gianni L: Triple-negative breast cancer: disease entity or title of convenience?. Nat Rev Clin Oncol. 2010, 7: 683-692. 10.1038/nrclinonc.2010.154.CrossRefPubMed
37.
Burga LN, Hu H, Juvekar A, Tung NM, Troyan SL, Hofstatter EW, Wulf GM: Loss of BRCA1 leads to an increase in epidermal growth factor receptor expression in mammary epithelial cells, and epidermal growth factor receptor inhibition prevents estrogen receptor-negative cancers in BRCA1-mutant mice. Breast Cancer Res. 2011, 13: R30-10.1186/bcr2850.CrossRefPubMedPubMedCentral
38.
Boominathan L: The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network. Cancer Metastasis Rev. 2010, 29: 613-639. 10.1007/s10555-010-9257-9.CrossRefPubMed
39.
Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ, Arking DE, Beer MA, Maitra A, Mendell JT: Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007, 26: 745-752. 10.1016/j.molcel.2007.05.010.CrossRefPubMedPubMedCentral
40.
Lujambio A, Calin GA, Villanueva A, Ropero S, Sánchez-Céspedes M, Blanco D, Montuenga LM, Rossi S, Nicoloso MS, Faller WJ, Gallagher WM, Eccles SA, Croce CM, Esteller M: A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA. 2008, 105: 13556-13561. 10.1073/pnas.0803055105.CrossRefPubMedPubMedCentral
41.
Lujambio A, Esteller M: CpG island hypermethylation of tumor suppressor microRNAs in human cancer. Cell Cycle. 2007, 6: 1455-1459.CrossRefPubMed
42.
Jordan VC: Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat Rev Cancer. 2007, 7: 46-53. 10.1038/nrc2048.CrossRefPubMed
43.
Royds JA, Iacopetta B: p53 and disease: when the guardian angel fails. Cell Death Differ. 2006, 13: 1017-1026. 10.1038/sj.cdd.4401913.CrossRefPubMed
44.
Bergh J, Norberg T, Sjögren S, Lindgren A, Holmberg L: Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nat Med. 1995, 1: 1029-1034. 10.1038/nm1095-1029.CrossRefPubMed
45.
Vousden KH, Prives C: p53 and prognosis: new insights and further complexity. Cell. 2005, 120: 7-10.PubMed
46.
Brown K: Is tamoxifen a genotoxic carcinogen in women?. Mutagenesis. 2009, 24: 391-404. 10.1093/mutage/gep022.CrossRefPubMed
47.
Roy PG, Thompson AM: Cyclin D1 and breast cancer. Breast. 2006, 15: 718-727. 10.1016/j.breast.2006.02.005.CrossRefPubMed
48.
Reedijk M, Pinnaduwage D, Dickson BC, Mulligan AM, Zhang H, Bull SB, O'Malley FP, Egan SE, Andrulis IL: JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer. Breast Cancer Res Treat. 2008, 111: 439-448. 10.1007/s10549-007-9805-3.CrossRefPubMed
Metadata
Title
miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells
Authors
Yee-Ming Lee
Jen-Yi Lee
Chao-Chi Ho
Qi-Sheng Hong
Sung-Liang Yu
Chii-Ruey Tzeng
Pan-Chyr Yang
Huei-Wen Chen
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2011
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3059

Other articles of this Issue 6/2011

Breast Cancer Research 6/2011 Go to the issue

Review

Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity

Research article

Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC - PACS 01 randomized trial

Research article

Regulation of breast cancer metastasis by Runx2 and estrogen signaling: the role of SNAI2

Research article

Opposing roles of CXCR4 and CXCR7 in breast cancer metastasis

Research article

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Research article

Different mechanisms for resistance to trastuzumab versus lapatinib in HER2- positive breast cancers - role of estrogen receptor and HER2 reactivation
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits