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
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2011

Open Access 01-12-2011 | Research

An integrative genomic analysis revealed the relevance of microRNA and gene expression for drug-resistance in human breast cancer cells

Authors: Yusuke Yamamoto, Yusuke Yoshioka, Kaho Minoura, Ryou-u Takahashi, Fumitaka Takeshita, Toshiki Taya, Reiko Horii, Yayoi Fukuoka, Takashi Kato, Nobuyoshi Kosaka, Takahiro Ochiya

Published in: Molecular Cancer | Issue 1/2011

Login to get access

Abstract

Background

Acquisition of drug-resistance in cancer has led to treatment failure, however, their mechanisms have not been clarified yet. Recent observations indicated that aberrant expressed microRNA (miRNA) caused by chromosomal alterations play a critical role in the initiation and progression of cancer. Here, we performed an integrated genomic analysis combined with array-based comparative hybridization, miRNA, and gene expression microarray to elucidate the mechanism of drug-resistance.

Results

Through genomic approaches in MCF7-ADR; a drug-resistant breast cancer cell line, our results reflect the unique features of drug-resistance, including MDR1 overexpression via genomic amplification and miRNA-mediated TP53INP1 down-regulation. Using a gain of function study with 12 miRNAs whose expressions were down-regulated and genome regions were deleted, we show that miR-505 is a novel tumor suppressive miRNA and inhibits cell proliferation by inducing apoptosis. We also find that Akt3, correlate inversely with miR-505, modulates drug sensitivity in MCF7-ADR.

Conclusion

These findings indicate that various genes and miRNAs orchestrate to temper the drug-resistance in cancer cells, and thus acquisition of drug-resistance is intricately controlled by genomic status, gene and miRNA expression changes.
Appendix
Available only for authorised users
Literature
1.
Tsuruo T, Naito M, Tomida A, Fujita N, Mashima T, Sakamoto H, Haga N: Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. Cancer Sci. 2003, 94: 15-21. 10.1111/j.1349-7006.2003.tb01345.xCrossRefPubMed
2.
Leslie EM, Deeley RG, Cole SP: Toxicological relevance of the multidrug resistance protein 1, MRP1 (ABCC1) and related transporters. Toxicology. 2001, 167: 3-23. 10.1016/S0300-483X(01)00454-1CrossRefPubMed
3.
Renes J, de Vries EG, Jansen PL, Muller M: The (patho)physiological functions of the MRP family. Drug Resist Updat. 2000, 3: 289-302. 10.1054/drup.2000.0156CrossRefPubMed
4.
Leonessa F, Clarke R: ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer. 2003, 10: 43-73. 10.1677/erc.0.0100043CrossRefPubMed
5.
6.
Esquela-Kerscher A, Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006, 6: 259-269. 10.1038/nrc1840CrossRefPubMed
7.
Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004, 116: 281-297. 10.1016/S0092-8674(04)00045-5CrossRefPubMed
8.
Calin GA, Croce CM: Chromosomal rearrangements and microRNAs: a new cancer link with clinical implications. J Clin Invest. 2007, 117: 2059-2066. 10.1172/JCI32577PubMedCentralCrossRefPubMed
9.
Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM: miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 2005, 102: 13944-13949. 10.1073/pnas.0506654102PubMedCentralCrossRefPubMed
10.
Wei JS, Song YK, Durinck S, Chen QR, Cheuk AT, Tsang P, Zhang Q, Thiele CJ, Slack A, Shohet J, Khan J: The MYCN oncogene is a direct target of miR-34a. Oncogene. 2008, 27: 5204-5213. 10.1038/onc.2008.154PubMedCentralCrossRefPubMed
11.
Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 2004, 101: 2999-3004. 10.1073/pnas.0307323101PubMedCentralCrossRefPubMed
12.
Iwao-Koizumi K, Matoba R, Ueno N, Kim SJ, Ando A, Miyoshi Y, Maeda E, Noguchi S, Kato K: Prediction of docetaxel response in human breast cancer by gene expression profiling. J Clin Oncol. 2005, 23: 422-431.CrossRefPubMed
13.
Honma K, Iwao-Koizumi K, Takeshita F, Yamamoto Y, Yoshida T, Nishio K, Nagahara S, Kato K, Ochiya T: RPN2 gene confers docetaxel resistance in breast cancer. Nat Med. 2008, 14: 939-948. 10.1038/nm.1858CrossRefPubMed
14.
Lipson D, Aumann Y, Ben-Dor A, Linial N, Yakhini Z: Efficient calculation of interval scores for DNA copy number data analysis. J Comput Biol. 2006, 13: 215-228. 10.1089/cmb.2006.13.215CrossRefPubMed
15.
16.
Ma S, Tang KH, Chan YP, Lee TK, Kwan PS, Castilho A, Ng I, Man K, Wong N, To KF, Zheng BJ, Lai PB, Lo CM, Chan KW, Guan XY: miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell. 2010, 7: 694-707. 10.1016/j.stem.2010.11.010CrossRefPubMed
17.
Gironella M, Seux M, Xie MJ, Cano C, Tomasini R, Gommeaux J, Garcia S, Nowak J, Yeung ML, Jeang KT, Chaix A, Fazli L, Motoo Y, Wang Q, Rocchi P, Russo A, Gleave M, Dagorn JC, Iovanna JL, Carrier A, Pébusque MJ, Dusetti NJ: Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci USA. 2007, 104: 16170-16175. 10.1073/pnas.0703942104PubMedCentralCrossRefPubMed
18.
Ito Y, Motoo Y, Yoshida H, Iovanna JL, Takamura Y, Miya A, Kuma K, Miyauchi A: Decreased expression of tumor protein p53-induced nuclear protein 1 (TP53INP1) in breast carcinoma. Anticancer Res. 2006, 26: 4391-4395.PubMed
19.
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM: A microRNA polycistron as a potential human oncogene. Nature. 2005, 435: 828-833. 10.1038/nature03552PubMedCentralCrossRefPubMed
20.
Sampath D, Calin GA, Puduvalli VK, Gopisetty G, Taccioli C, Liu CG, Ewald B, Liu C, Keating MJ, Plunkett W: Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase Itch for degradation. Blood. 2009, 113: 3744-3753. 10.1182/blood-2008-09-178707PubMedCentralCrossRefPubMed
21.
Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ: RAS is regulated by the let-7 microRNA family. Cell. 2005, 120: 635-647. 10.1016/j.cell.2005.01.014CrossRefPubMed
22.
Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J, Song E: let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007, 131: 1109-1123. 10.1016/j.cell.2007.10.054CrossRefPubMed
23.
Mayr C, Hemann MT, Bartel DP: Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science. 2007, 315: 1576-1579. 10.1126/science.1137999PubMedCentralCrossRefPubMed
24.
Cheung M, Sharma A, Madhunapantula SV, Robertson GP: Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development. Cancer Res. 2008, 68: 3429-3439. 10.1158/0008-5472.CAN-07-5867PubMedCentralCrossRefPubMed
25.
Cristiano BE, Chan JC, Hannan KM, Lundie NA, Marmy-Conus NJ, Campbell IG, Phillips WA, Robbie M, Hannan RD, Pearson RB: A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)-M phase transition. Cancer Res. 2006, 66: 11718-11725. 10.1158/0008-5472.CAN-06-1968CrossRefPubMed
26.
Calin GA, Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 2006, 6: 857-866. 10.1038/nrc1997CrossRefPubMed
27.
Vivanco I, Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002, 2: 489-501. 10.1038/nrc839CrossRefPubMed
28.
Yuan XJ, Whang YE: PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway. Oncogene. 2002, 21: 319-327. 10.1038/sj.onc.1205054CrossRefPubMed
29.
Wan X, Yokoyama Y, Shinohara A, Takahashi Y, Tamaya T: PTEN augments staurosporine-induced apoptosis in PTEN-null Ishikawa cells by downregulating PI3K/Akt signaling pathway. Cell Death Differ. 2002, 9: 414-420. 10.1038/sj.cdd.4400982CrossRefPubMed
30.
Grady WM, Parkin RK, Mitchell PS, Lee JH, Kim YH, Tsuchiya KD, Washington MK, Paraskeva C, Willson JK, Kaz AM, Kroh EM, Allen A, Fritz BR, Markowitz SD, Tewari M: Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer. Oncogene. 2008, 27: 3880-3888. 10.1038/onc.2008.10CrossRefPubMed
31.
Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA, Jones PA: Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell. 2006, 9: 435-443. 10.1016/j.ccr.2006.04.020CrossRefPubMed
32.
Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T: Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007, 39: 673-677. 10.1038/ng2003CrossRefPubMed
33.
Pedersen IM, Cheng G, Wieland S, Volinia S, Croce CM, Chisari FV, David M: Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature. 2007, 449: 919-922. 10.1038/nature06205PubMedCentralCrossRefPubMed
34.
Mitelman F, Mertens F, Johansson B: A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nat Genet. 1997, 15 (Spec No): 417-474.CrossRefPubMed
35.
Simoneau M, Aboulkassim TO, LaRue H, Rousseau F, Fradet Y: Four tumor suppressor loci on chromosome 9q in bladder cancer: evidence for two novel candidate regions at 9q22.3 and 9q31. Oncogene. 1999, 18: 157-163. 10.1038/sj.onc.1202277CrossRefPubMed
36.
Sinha S, Singh RK, Alam N, Roy A, Roychoudhury S, Panda CK: Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: pathological significance in early- and late-onset breast carcinoma. Mol Cancer. 2008, 7: 84- 10.1186/1476-4598-7-84PubMedCentralCrossRefPubMed
37.
Tsuchiya Y, Nakajima M, Takagi S, Taniya T, Yokoi T: MicroRNA regulates the expression of human cytochrome P450 1B1. Cancer Res. 2006, 66: 9090-9098. 10.1158/0008-5472.CAN-06-1403CrossRefPubMed
38.
Wang Y, Rathinam R, Walch A, Alahari SK: ST14 (suppression of tumorigenicity 14) gene is a target for miR-27b, and the inhibitory effect of ST14 on cell growth is independent of miR-27b regulation. J Biol Chem. 2009, 284: 23094-23106. 10.1074/jbc.M109.012617PubMedCentralCrossRefPubMed
39.
Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D, So CW: beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell. 18: 606-618.
40.
Bjorklund CC, Ma W, Wang ZQ, Davis RE, Kuhn DJ, Kornblau SM, Wang M, Shah JJ, Orlowski RZ: Evidence of a Role for Activation of Wnt/{beta}-Catenin Signaling in the Resistance of Plasma Cells to Lenalidomide. J Biol Chem. 286: 11009-11020.
41.
Senthivinayagam S, Mishra P, Paramasivam SK, Yallapragada S, Chatterjee M, Wong L, Rana A, Rana B: Caspase-mediated cleavage of beta-catenin precedes drug-induced apoptosis in resistant cancer cells. J Biol Chem. 2009, 284: 13577-13588. 10.1074/jbc.M900248200PubMedCentralCrossRefPubMed
42.
Zhang X, Wang T, Batist G, Tsao MS: Transforming growth factor beta 1 promotes spontaneous transformation of cultured rat liver epithelial cells. Cancer Res. 1994, 54: 6122-6128.PubMed
43.
Caja L, Sancho P, Bertran E, Iglesias-Serret D, Gil J, Fabregat I: Overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-{beta}-induced cell death through impairing up-regulation of the NADPH oxidase NOX4. Cancer Res. 2009, 69: 7595-7602. 10.1158/0008-5472.CAN-09-1482CrossRefPubMed
Metadata
Title
An integrative genomic analysis revealed the relevance of microRNA and gene expression for drug-resistance in human breast cancer cells
Authors
Yusuke Yamamoto
Yusuke Yoshioka
Kaho Minoura
Ryou-u Takahashi
Fumitaka Takeshita
Toshiki Taya
Reiko Horii
Yayoi Fukuoka
Takashi Kato
Nobuyoshi Kosaka
Takahiro Ochiya
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2011
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-10-135

Other articles of this Issue 1/2011

Molecular Cancer 1/2011 Go to the issue

Review

Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?

Research

Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells

Research

Epigenetic markers for early detection of nasopharyngeal carcinoma in a high risk population

Review

Metastasis: new perspectives on an old problem

Research

Kinome expression profiling and prognosis of basal breast cancers

Research

Possible role of death receptor-mediated apoptosis by the E3 ubiquitin ligases Siah2 and POSH
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