Top

Published in:

01-05-2014 | Original Article

Overexpression of metadherin/MTDH is associated with an aggressive phenotype and a poor prognosis in invasive breast cancer

Authors: Eriko Tokunaga, Yuichiro Nakashima, Nami Yamashita, Yuichi Hisamatsu, Satoko Okada, Sayuri Akiyoshi, Shinichi Aishima, Hiroyuki Kitao, Masaru Morita, Yoshihiko Maehara

Published in: Breast Cancer | Issue 3/2014

Abstract

Background

Metadherin (MTDH) plays functional roles in the tumorigenesis and tumor progression of various cancers. This study investigated the associations between MTDH and the clinicopathological features in primary breast carcinomas to clarify the role of MTDH in the phenotypes and prognosis of breast cancer.

Methods

A total of 195 primary invasive breast cancer samples were evaluated. The MTDH DNA copy number and MTDH mRNA expression were analyzed by quantitative genomic polymerase chain reaction (PCR) and quantitative reverse transcriptase PCR. MTDH protein expression was analyzed by immunohistochemistry.

Results

A positive correlation was found between the expression of MTDH protein and mRNA expression and the MTDH DNA copy number. MTDH overexpression was significantly associated with a high nuclear grade, negative estrogen receptor (ER) and progesterone receptor (PR) expression, high Ki67 index, poor disease-free survival (P = 0.0001), poor distant metastasis-free survival (P = 0.009), and poor overall survival (P = 0.0101). MTDH overexpression showed a particularly negative impact on the prognosis in node-negative patients. A multivariate analysis showed MTDH overexpression to be independently associated with a poor disease-free survival rate [HR 3.45, 95 % confidence interval (CI) 1.69–6.84, P = 0.0010] and a poor distant metastasis-free survival rate (HR 2.39, 95 % CI 1.08–5.01, P = 0.0319).

Conclusion

MTDH overexpression contributes to an aggressive phenotype, thus leading to a poor prognosis for primary invasive breast cancer.

Hortobagyi GN, de la Garza Salazar J, Pritchard K, Amadori D, Haidinger R, Hudis CA, et al. The global breast cancer burden: variations in epidemiology and survival. Clin Breast Cancer. 2005;6:391–401.PubMedCrossRef

Shin HR, Boniol M, Joubert C, Hery C, Haukka J, Autier P, et al. Secular trends in breast cancer mortality in five East Asian populations: Hong Kong, Japan, Korea, Singapore and Taiwan. Cancer Sci. 2010;101:1241–6.PubMedCrossRef

Qiu D, Katanoda K, Marugame T, Sobue T. A joinpoint regression analysis of long-term trends in cancer mortality in Japan (1958–2004). Int J Cancer. 2009;124:443–8.PubMedCrossRef

Su ZZ, Kang DC, Chen Y, Pekarskaya O, Chao W, Volsky DJ, et al. Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH. Oncogene. 2002;21:3592–602.PubMedCrossRef

Brown DM, Ruoslahti E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell. 2004;5:365–74.PubMedCrossRef

Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, et al. MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell. 2009;15:9–20.PubMedCrossRefPubMedCentral

Kang DC, Su ZZ, Sarkar D, Emdad L, Volsky DJ, Fisher PB. Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. Gene. 2005;353:8–15.PubMedCrossRef

Warr T, Ward S, Burrows J, Harding B, Wilkins P, Harkness W, et al. Identification of extensive genomic loss and gain by comparative genomic hybridisation in malignant astrocytoma in children and young adults. Genes Chromosom Cancer. 2001;31:15–22.PubMedCrossRef

Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, Mukhopadhyay ND, et al. Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest. 2009;119:465–77.PubMedCrossRefPubMedCentral

10.

Li J, Zhang N, Song LB, Liao WT, Jiang LL, Gong LY, et al. Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival. Clin Cancer Res. 2008;14:3319–26.PubMedCrossRef

11.

Liu H, Song X, Liu C, Xie L, Wei L, Sun R. Knockdown of astrocyte elevated gene-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells. J Exp Clin Cancer Res. 2009;28:19.PubMedCrossRefPubMedCentral

12.

Song L, Li W, Zhang H, Liao W, Dai T, Yu C, et al. Over-expression of AEG-1 significantly associates with tumour aggressiveness and poor prognosis in human non-small cell lung cancer. J Pathol. 2009;219:317–26.PubMedCrossRef

13.

Su P, Zhang Q, Yang Q. Immunohistochemical analysis of metadherin in proliferative and cancerous breast tissue. Diagn Pathol. 2010;5:38.PubMedCrossRefPubMedCentral

14.

Tokunaga E, Oki E, Oda S, Kataoka A, Kitamura K, Ohno S, et al. Frequency of microsatellite instability in breast cancer determined by high-resolution fluorescent microsatellite analysis. Oncology. 2000;59:44–9.PubMedCrossRef

15.

Tokunaga E, Kimura Y, Oki E, Ueda N, Futatsugi M, Mashino K, et al. Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. Int J Cancer. 2006;118:284–9.PubMedCrossRef

16.

Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol. 2008;26:2373–8.PubMedCrossRef

17.

Ash SC, Yang DQ, Britt DE. LYRIC/AEG-1 overexpression modulates BCCIPalpha protein levels in prostate tumor cells. Biochem Biophys Res Commun. 2008;371:333–8.PubMedCrossRefPubMedCentral

18.

Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K, et al. Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res. 2006;66:1509–16.PubMedCrossRef

19.

Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, et al. Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene. 2007;26:7647–55.PubMedCrossRef

20.

Kwong LN, Chin L. The metastasis problem gets stickier. Cancer Cell. 2009;15:1–2.PubMedCrossRef

21.

Sarkar D, Park ES, Emdad L, Lee SG, Su ZZ, Fisher PB. Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. Cancer Res. 2008;68:1478–84.PubMedCrossRef

22.

Thirkettle HJ, Girling J, Warren AY, Mills IG, Sahadevan K, Leung H, et al. LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals. Clin Cancer Res. 2009;15:3003–13.PubMedCrossRef

23.

Yu C, Chen K, Zheng H, Guo X, Jia W, Li M, et al. Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis. Carcinogenesis. 2009;30:894–901.PubMedCrossRef

24.

Hu G, Wei Y, Kang Y. The multifaceted role of MTDH/AEG-1 in cancer progression. Clin Cancer Res. 2009;15:5615–20.PubMedCrossRefPubMedCentral

25.

Sarkar D, Emdad L, Lee SG, Yoo BK, Su ZZ, Fisher PB. Astrocyte elevated gene-1: far more than just a gene regulated in astrocytes. Cancer Res. 2009;69:8529–35.PubMedCrossRefPubMedCentral

26.

Tokunaga E, Oki E, Nishida K, Koga T, Egashira A, Morita M, et al. Trastuzumab and breast cancer: developments and current status. Int J Clin Oncol. 2006;11:199–208.PubMedCrossRef

27.

Jones KL, Buzdar AU. Evolving novel anti-HER2 strategies. Lancet Oncol. 2009;10:1179–87.PubMedCrossRef

28.

Yamashita H. Current research topics in endocrine therapy for breast cancer. Int J Clin Oncol. 2008;13:380–3.PubMedCrossRef

29.

Li J, Yang L, Song L, Xiong H, Wang L, Yan X, et al. Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1. Oncogene. 2009;28:3188–96.PubMedCrossRef

30.

Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 2009;20:1319–29.PubMedCrossRefPubMedCentral

31.

Sutherland HG, Lam YW, Briers S, Lamond AI, Bickmore WA. 3D3/lyric: a novel transmembrane protein of the endoplasmic reticulum and nuclear envelope, which is also present in the nucleolus. Exp Cell Res. 2004;294:94–105.PubMedCrossRef

Title: Overexpression of metadherin/MTDH is associated with an aggressive phenotype and a poor prognosis in invasive breast cancer
Authors: Eriko Tokunaga
Yuichiro Nakashima
Nami Yamashita
Yuichi Hisamatsu
Satoko Okada
Sayuri Akiyoshi
Shinichi Aishima
Hiroyuki Kitao
Masaru Morita
Yoshihiko Maehara
Publication date: 01-05-2014
Publisher: Springer Japan
Published in: Breast Cancer / Issue 3/2014
Print ISSN: 1340-6868
Electronic ISSN: 1880-4233
DOI: https://doi.org/10.1007/s12282-012-0398-2

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2014

A case report of pigmented mammary Paget’s disease mimicking nevus of the nipple

MRI volume measurements compared with the RECIST 1.1 for evaluating the response to neoadjuvant chemotherapy for mass-type lesions

A novel taspine derivative, HMQ1611, suppresses adhesion, migration and invasion of ZR-75-30 human breast cancer cells

Analysis of clinically relevant values of Ki-67 labeling index in Japanese breast cancer patients

Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer

Reversine induces cell cycle arrest, polyploidy, and apoptosis in human breast cancer cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer