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
Breast Cancer Research
Published in: Breast Cancer Research 3/2012

Open Access 01-06-2012 | Research article

JMJD6 is a driver of cellular proliferation and motility and a marker of poor prognosis in breast cancer

Authors: Yi Fang Lee, Lance David Miller, Xiu Bin Chan, Michael A Black, Brendan Pang, Chee Wee Ong, Manuel Salto-Tellez, Edison T Liu, Kartiki V Desai

Published in: Breast Cancer Research | Issue 3/2012

Login to get access

Abstract

Introduction

We developed an analytic strategy that correlates gene expression and clinical outcomes as a means to identify novel candidate oncogenes operative in breast cancer. This analysis, followed by functional characterization, resulted in the identification of Jumonji Domain Containing 6 (JMJD6) protein as a novel driver of oncogenic properties in breast cancer.

Methods

Through microarray informatics, Cox proportional hazards regression was used to analyze the correlation between gene expression and distant metastasis-free survival (DMFS) of patients in 14 independent breast cancer cohorts. JMJD6 emerged as a top candidate gene robustly associated with poor patient survival. Immunohistochemistry, siRNA-mediated silencing, and forced overexpression of JMJD6 in cell-based assays elucidated molecular mechanisms of JMJD6 action in breast cancer progression and shed light on the clinical breast cancer subtypes relevant to JMJD6 action.

Results

JMJD6 was expressed at highest levels in tumors associated with worse outcomes, including ER- and basal-like, Claudin-low, Her2-enriched, and ER+ Luminal B tumors. High nuclear JMJD6 protein was associated with ER negativity, advanced grade, and poor differentiation in tissue microarrays. Separation of ER+/LN- patients that received endocrine monotherapy indicated that JMJD6 is predictive of poor outcome in treatment-specific subgroups. In breast cancer cell lines, loss of JMJD6 consistently resulted in suppressed proliferation but not apoptosis, whereas forced stable overexpression increased growth. In addition, knockdown of JMJD6 in invasive cell lines, such as MDA-MB231, decreased motility and invasion, whereas overexpression in MCF-7 cells slightly promoted motility but did not confer invasive growth. Microarray analysis showed that the most significant transcriptional changes occurred in cell-proliferation genes and genes of the TGF-β tumor-suppressor pathway. High proliferation was characterized by constitutively high cyclin E protein levels. The inverse relation of JMJD6 expression with TGF-β 2 could be extrapolated to the breast cancer cohorts, suggesting that JMJD6 may affect similar pathways in primary breast cancer.

Conclusions

JMJD6 is a novel biomarker of tumor aggressiveness with functional implications in breast cancer growth and migration.
Appendix
Available only for authorised users
Literature
1.
Soon WWML, Black MA, Dalmasso C, Chan XB, Pang B, Ong CW, Salto-Tellez M, Desai K, Liu ET: Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer. EMBO Mol Med 2011, 3:451–464.CrossRefPubMedPubMedCentral
2.
Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RAB, Henson PM: A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 2000, 405:85–90.CrossRefPubMed
3.
Bose J, Gruber A, Helming L, Schiebe S, Wegener I, Hafner M, Beales M, Kontgen F, Lengeling A: The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal. J Biol 2004, 3:15.CrossRefPubMedPubMedCentral
4.
Cui P, Qin B, Liu N, Pan G, Pei D: Nuclear localization of the phosphatidylserine receptor protein via multiple nuclear localization signals. Exp Cell Res 2004, 293:154–163.CrossRefPubMed
5.
Chang B, Chen Y, Zhao Y, Bruick RK: JMJD6 Is a histone arginine demethylase. Science 2007, 318:444–447.CrossRefPubMed
6.
Webby CJ, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B, Nielsen ML, Schmitz C, Butler DS, Yates JR, Delahunty CM, Hahn P, Lengeling A, Mann M, Proudfoot NJ, Schofield CJ, Böttger A: Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science 2009, 325:90–93.CrossRefPubMed
7.
Boeckel J-N, Guarani V, Koyanagi M, Roexe T, Lengeling A, Schermuly RT, Gellert P, Braun T, Zeiher A, Dimmeler S: Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1. Proc Natl Acad Sci USA 2011, 108:3276–3281.CrossRefPubMedPubMedCentral
8.
Hong X, Zang J, White J, Wang C, Pan CH, Zhao R, Murphy RC, Dai S, Henson P, Kappler JW, Hagman J, Zhang G: Interaction of JMJD6 with single-stranded RNA. Proc Natl Acad Sci USA 2010, 107:14568–14572.CrossRefPubMedPubMedCentral
9.
Team RDC: R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing. 2010.
10.
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY, Zhang J: Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004, 5:R80.CrossRefPubMedPubMedCentral
11.
Li C, Rabinovic A: Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 2007, 8:118–127.CrossRefPubMed
12.
Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS: Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 2009, 27:1160–1167.CrossRefPubMedPubMedCentral
13.
14.
Prat A, Parker J, Karginova O, Fan C, Livasy C, Herschkowitz J, He X, Perou C: Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 2010, 12:R68.CrossRefPubMedPubMedCentral
15.
SigmaPlot for Windows 11.0th edition. Systat Software, Inc., San Jose, CA; 2008.
16.
Salto-Tellez M, Nga ME, Han HC, Wong AS, Lee CK, Anuar D, Ng SS, Ho M, Wee A, Chan YH, Soong R: Tissue microarrays characterise the clinical significance of a VEGF-A protein expression signature in gastrointestinal stromal tumours. Br J Cancer 2007, 96:776–782.CrossRefPubMedPubMedCentral
17.
Das K, Mohd Omar MF, Ong CW, Bin Abdul Rashid S, Peh BK, Putti TC, Tan PH, Chia KS, Teh M, Shah N, Soong R, Salto-Tellez M: TRARESA: a tissue microarray-based hospital system for biomarker validation and discovery. Pathology 2008, 40:441–449.CrossRefPubMed
18.
PASW Statistics 18 18.0.0 edition. Chicago: SPSS Inc.; 2009.
19.
Shtutman M, Levina E, Ohouo P, Baig M, Roninson IB: Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases scattering and motility of MCF7 breast carcinoma cells. Cancer Res 2006, 66:11370–11380.CrossRefPubMed
20.
21.
Eisen MB, Spellman PT, Brown PO, Botstein D: Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998, 95:14863–14868.CrossRefPubMedPubMedCentral
22.
23.
Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM: Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 2007, 8:R76.CrossRefPubMedPubMedCentral
24.
Sørlie T: Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer 2004, 40:2667–2675.CrossRefPubMed
25.
26.
Robson CN, Gnanapragasam V, Byrne RL, Collins AT, Neal DE: Transforming growth factor-beta1 up-regulates p15, p21 and p27 and blocks cell cycling in G1 in human prostate epithelium. J Endocrinol 1999, 160:257–266.CrossRefPubMed
27.
Ravitz MJWC: Cyclin-dependent kinase regulation during G1 phase and cell cycle regulation by TGF-beta. Adv Cancer Res 1997, 71:165–207.CrossRefPubMed
28.
Arteaga CL, Hurd SD, Winnier AR, Johnson MD, Fendly BM, Forbes JT: Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity: implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression. J Clin Invest 1993, 92:2569–2576.CrossRefPubMedPubMedCentral
29.
Ji H, Stout LE, Zhang Q, Zhang R, Leung HT, Leung BS: Absence of transforming growth factor-beta responsiveness in the tamoxifen growth-inhibited human breast cancer cell line CAMA-1. J Cell Biochem 1994, 54:332–342.CrossRefPubMed
30.
Fanayan S, Firth SM, Butt AJ, Baxter RC: Growth inhibition by insulin-like growth factor-binding protein-3 in T47D breast cancer cells requires transforming growth factor-β(TGF-β) and the type II TGF-β receptor. J Biol Chem 2000, 275:39146–39151.CrossRefPubMed
31.
Chen CR, Kang Y, Massagué J: Defective repression of c-myc in breast cancer cells: a loss at the core of the transforming growth factor β growth arrest program. Proc Natl Acad Sci USA 2001, 98:992–999.CrossRefPubMedPubMedCentral
32.
Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T: TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 1997, 124:2659–2670.PubMedPubMedCentral
33.
Geng Y, Weinberg RA: Transforming growth factor beta effects on expression of G1 cyclins and cyclin-dependent protein kinases. Proc Natl Acad Sci USA 1993, 90:10315–10319.CrossRefPubMedPubMedCentral
34.
Moustakas A, Pardali K, Gaal A, Heldin C-H: Mechanisms of TGF-[beta] signaling in regulation of cell growth and differentiation. Immunol Lett 2002, 82:85–91.CrossRefPubMed
35.
Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF: Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci USA 1995, 92:5545–5549.CrossRefPubMedPubMedCentral
36.
Keyomarsi K, Tucker SL, Buchholz TA, Callister M, Ding Y, Hortobagyi GN, Bedrosian I, Knickerbocker C, Toyofuku W, Lowe M, Herliczek TW, Bacus SS: Cyclin E and survival in patients with breast cancer. N Engl J Med 2002, 347:1566–1575.CrossRefPubMed
37.
Spruck CH, Won K-A, Reed SI: Deregulated cyclin E induces chromosome instability. Nature 1999, 401:297–300.CrossRefPubMed
38.
Scaltriti M, Eichhorn PJ, Cortés J, Prudkin L, Aura C, Jiménez J, Chandarlapaty S, Serra V, Prat A, Ibrahim YH, Guzmán M, Gili M, Rodríguez O, Rodríguez S, Pérez J, Green SR, Mai S, Rosen N, Hudis C, Baselga J: Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc Natl Acad Sci USA 2011, 108:3761–3766.CrossRefPubMedPubMedCentral
Metadata
Title
JMJD6 is a driver of cellular proliferation and motility and a marker of poor prognosis in breast cancer
Authors
Yi Fang Lee
Lance David Miller
Xiu Bin Chan
Michael A Black
Brendan Pang
Chee Wee Ong
Manuel Salto-Tellez
Edison T Liu
Kartiki V Desai
Publication date
01-06-2012
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 3/2012
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3200

Other articles of this Issue 3/2012

Breast Cancer Research 3/2012 Go to the issue

Research article

Phosphorylated and sumoylation-deficient progesterone receptors drive proliferative gene signatures during breast cancer progression

Review

Challenges and opportunities in the targeting of fibroblast growth factor receptors in breast cancer

Research article

Local-regional control according to surrogate markers of breast cancer subtypes and response to neoadjuvant chemotherapy in breast cancer patients undergoing breast conserving therapy

Research article

Loss of plakoglobin promotes decreased cell-cell contact, increased invasion, and breast cancer cell dissemination in vivo

Research article

Invasive breast cancer induces laminin-332 upregulation and integrin β4 neoexpression in myofibroblasts to confer an anoikis-resistant phenotype during tissue remodeling

Research article

Downregulation of the tumor-suppressor miR-16 via progestin-mediated oncogenic signaling contributes to breast cancer development
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