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
BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

MTDH mediates trastuzumab resistance in HER2 positive breast cancer by decreasing PTEN expression through an NFκB-dependent pathway

Authors: Cheng Du, Xiaomin Yi, Wenchao Liu, Tao Han, Zhaozhe Liu, Zhenyu Ding, Zhendong Zheng, Ying Piao, Jianlin Yuan, Yaling Han, Manjiang Xie, Xiaodong Xie

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

Background

Trastuzumab resistance is almost inevitable in the management of human epidermal growth factor receptor (HER) 2 positive breast cancer, in which phosphatase and tensin homolog deleted from chromosome 10 (PTEN) loss is implicated. Since metadherin (MTDH) promotes malignant phenotype of breast cancer, we sought to define whether MTDH promotes trastuzumab resistance by decreasing PTEN expression through an NFκB-dependent pathway.

Methods

The correlations between MTDH and PTEN expressions were analyzed both in HER2 positive breast cancer tissues and trastuzumab resistant SK-BR-3 (SK-BR-3/R) cells. Gene manipulations of MTDH and PTEN levels by knockdown or overexpression were utilized to elucidate molecular mechanisms of MTDH and PTEN implication in trastuzumab resistance. For in vivo studies, SK-BR-3 and SK-BR-3/R cells and modified derivatives were inoculated into nude mice alone or under trastuzumab exposure. Tumor volumes, histological examinations as well as Ki67 and PTEN expressions were revealed.

Results

Elevated MTDH expression indicated poor clinical benefit, shortened progression free survival time, and was negatively correlated with PTEN level both in HER2 positive breast cancer patients and SK-BR-3/R cells. MTDH knockdown restored PTEN expression and trastuzumab sensitivity in SK-BR-3/R cells, while MTDH overexpression prevented SK-BR-3 cell death under trastuzumab exposure, probably through IκBα inhibition and nuclear translocation of p65 which subsequently decreased PTEN expression. Synergized effect of PTEN regulation were observed upon MTDH and p65 co-transfection. Forced PTEN expression in SK-BR-3/R cells restored trastuzumab sensitivity. Furthermore, decreased tumor volume and Ki67 level as well as increased PTEN expression were observed after MTDH knockdown in subcutaneous breast cancer xenografts from SK-BR-3/R cells, while the opposite effect were found in grafts from MTDH overexpressing SK-BR-3 cells.

Conclusions

MTDH overexpression confers trastuzumab resistance in HER2 positive breast cancer. MTDH mediates trastuzumab resistance, at least in part, by PTEN inhibition through an NFκB-dependent pathway, which may be utilized as a promising therapeutic target for HER2 positive breast cancer.
Appendix
Available only for authorised users
Literature
1.
Tsang RY, Finn RS: Beyond trastuzumab: novel therapeutic strategies in HER2-positive metastatic breast cancer. Br J Cancer. 2012, 106 (1): 6-13. 10.1038/bjc.2011.516.CrossRefPubMedPubMedCentral
2.
Moasser MM: The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007, 26 (45): 6469-6487. 10.1038/sj.onc.1210477.CrossRefPubMedPubMedCentral
3.
Ayyappan S, Prabhakar D, Sharma N: Epidermal growth factor receptor (EGFR)-targeted therapies in esophagogastric cancer. Anticancer Res. 2013, 33 (10): 4139-4155.PubMed
4.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987, 235 (4785): 177-182. 10.1126/science.3798106.CrossRefPubMed
5.
Capelan M, Pugliano L, De Azambuja E, Bozovic I, Saini KS, Sotiriou C, Loi S, Piccart-Gebhart MJ: Pertuzumab: new hope for patients with HER2-positive breast cancer. Ann Oncol. 2013, 24 (2): 273-282. 10.1093/annonc/mds328.CrossRefPubMed
6.
Hudis CA: Trastuzumab–mechanism of action and use in clinical practice. N Engl J Med. 2007, 357 (1): 39-51. 10.1056/NEJMra043186.CrossRefPubMed
7.
Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008, 26 (10): 1642-1649. 10.1200/JCO.2007.11.6699.CrossRefPubMed
8.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005, 353 (16): 1673-1684. 10.1056/NEJMoa052122.CrossRefPubMed
9.
10.
Mohd Sharial MS, Crown J, Hennessy BT: Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer. Ann Oncol. 2012, 23 (12): 3007-3016. 10.1093/annonc/mds200.CrossRefPubMedPubMedCentral
11.
Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L: Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2012, 9 (1): 16-32.CrossRef
12.
Su ZZ, Kang DC, Chen Y, Pekarskaya O, Chao W, Volsky DJ, Fisher PB: 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 (22): 3592-3602. 10.1038/sj.onc.1205445.CrossRefPubMed
13.
Blanco MA, Aleckovic M, Hua Y, Li T, Wei Y, Xu Z, Cristea IM, Kang Y: Identification of staphylococcal nuclease domain-containing 1 (SND1) as a Metadherin-interacting protein with metastasis-promoting functions. J Biol Chem. 2011, 286 (22): 19982-19992. 10.1074/jbc.M111.240077.CrossRefPubMedPubMedCentral
14.
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 (1): 8-15. 10.1016/j.gene.2005.04.006.CrossRefPubMed
15.
Lee SG, Kang DC, DeSalle R, Sarkar D, Fisher PB: AEG-1/MTDH/LYRIC, the beginning: initial cloning, structure, expression profile, and regulation of expression. Adv Cancer Res. 2013, 120: 1-38.CrossRefPubMedPubMedCentral
16.
Yoo BK, Emdad L, Lee SG, Su ZZ, Santhekadur P, Chen D, Gredler R, Fisher PB, Sarkar D: Astrocyte elevated gene-1 (AEG-1): A multifunctional regulator of normal and abnormal physiology. Pharmacol Ther. 2011, 130 (1): 1-8. 10.1016/j.pharmthera.2011.01.008.CrossRefPubMedPubMedCentral
17.
Liu HY, Liu CX, Han B, Zhang XY, Sun RP: AEG-1 is associated with clinical outcome in neuroblastoma patients. Cancer Biomark. 2012, 11 (2–3): 115-121.PubMed
18.
Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, Place RF, Pookot D, Majid S, Igawa M, Dahiya R: Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene. 2007, 26 (55): 7647-7655. 10.1038/sj.onc.1210572.CrossRefPubMed
19.
Tokunaga E, Nakashima Y, Yamashita N, Hisamatsu Y, Okada S, Akiyoshi S, Aishima S, Kitao H, Morita M, Maehara Y: Overexpression of metadherin/MTDH is associated with an aggressive phenotype and a poor prognosis in invasive breast cancer. Breast Cancer. 2014, 21 (3): 341-349. 10.1007/s12282-012-0398-2.CrossRefPubMed
20.
Meng X, Brachova P, Yang S, Xiong Z, Zhang Y, Thiel KW, Leslie KK: Knockdown of MTDH sensitizes endometrial cancer cells to cell death induction by death receptor ligand TRAIL and HDAC inhibitor LBH589 co-treatment. PLoS One. 2011, 6 (6): e20920-10.1371/journal.pone.0020920.CrossRefPubMedPubMedCentral
21.
22.
Heo J, Lim CK, Whang DR, Shin J, Jeong SY, Park SY, Kwon IC, Kim S: Self-deprotonation and colorization of 1,3-bis(dicyanomethylidene)indan in polar media: a facile route to a minimal polymethine dye for NIR fluorescence imaging. Chemistry. 2012, 18 (28): 8699-8704. 10.1002/chem.201103042.CrossRefPubMed
23.
Wan L, Kang Y: Pleiotropic roles of AEG-1/MTDH/LYRIC in breast cancer. Adv Cancer Res. 2013, 120: 113-134.CrossRefPubMed
24.
Emdad L, Das SK, Dasgupta S, Hu B, Sarkar D, Fisher PB: AEG-1/MTDH/LYRIC: signaling pathways, downstream genes, interacting proteins, and regulation of tumor angiogenesis. Adv Cancer Res. 2013, 120: 75-111.CrossRefPubMedPubMedCentral
25.
Moelans CB, van der Groep P, Hoefnagel LD, van de Vijver MJ, Wesseling P, Wesseling J, van der Wall E, van Diest PJ: Genomic evolution from primary breast carcinoma to distant metastasis: Few copy number changes of breast cancer related genes. Cancer Lett. 2014, 344 (1): 138-146. 10.1016/j.canlet.2013.10.025.CrossRefPubMed
26.
Yi X, Zhang G, Yuan J: Renoprotective role of fenoldopam pretreatment through hypoxia-inducible factor-1alpha and heme oxygenase-1 expressions in rat kidney transplantation. Transplant Proc. 2013, 45 (2): 517-522. 10.1016/j.transproceed.2012.02.051.CrossRefPubMed
27.
Li J, Zhang N, Song LB, Liao WT, Jiang LL, Gong LY, Wu J, Yuan J, Zhang HZ, Zeng MS, Li M: Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival. Clin Cancer Res. 2008, 14 (11): 3319-3326. 10.1158/1078-0432.CCR-07-4054.CrossRefPubMed
28.
Yoo BK, Gredler R, Vozhilla N, Su ZZ, Chen D, Forcier T, Shah K, Saxena U, Hansen U, Fisher PB, Sarkar D: Identification of genes conferring resistance to 5-fluorouracil. Proc Natl Acad Sci U S A. 2009, 106 (31): 12938-12943. 10.1073/pnas.0901451106.CrossRefPubMedPubMedCentral
29.
Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, Reiss M, Au JL, Haffty BG, Kang Y: MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell. 2009, 15 (1): 9-20. 10.1016/j.ccr.2008.11.013.CrossRefPubMedPubMedCentral
30.
Zhang N, Wang X, Huo Q, Li X, Wang H, Schneider P, Hu G, Yang Q: The oncogene metadherin modulates the apoptotic pathway based on the tumor necrosis factor superfamily member TRAIL (Tumor Necrosis Factor-related Apoptosis-inducing Ligand) in breast cancer. J Biol Chem. 2013, 288 (13): 9396-9407. 10.1074/jbc.M112.395913.CrossRefPubMedPubMedCentral
31.
Gong C, Yao Y, Wang Y, Liu B, Wu W, Chen J, Su F, Yao H, Song E: Up-regulation of miR-21 mediates resistance to trastuzumab therapy for breast cancer. J Biol Chem. 2011, 286 (21): 19127-19137. 10.1074/jbc.M110.216887.CrossRefPubMedPubMedCentral
32.
De P, Hasmann M, Leyland-Jones B: Molecular determinants of trastuzumab efficacy: What is their clinical relevance?. Cancer Treat Rev. 2013, 39 (8): 925-934. 10.1016/j.ctrv.2013.02.006.CrossRefPubMed
33.
Kumler I, Tuxen MK, Nielsen DL: A systematic review of dual targeting in HER2-positive breast cancer. Cancer Treat Rev. 2014, 40 (2): 259-270. 10.1016/j.ctrv.2013.09.002.CrossRefPubMed
34.
Su P, Zhang Q, Yang Q: Immunohistochemical analysis of Metadherin in proliferative and cancerous breast tissue. Diagn Pathol. 2010, 5: 38-10.1186/1746-1596-5-38.CrossRefPubMedPubMedCentral
35.
Li C, Li R, Song H, Wang D, Feng T, Yu X, Zhao Y, Liu J, Yu X, Wang Y, Geng J: Significance of AEG-1 expression in correlation with VEGF, microvessel density and clinicopathological characteristics in triple-negative breast cancer. J Surg Oncol. 2011, 103 (2): 184-192. 10.1002/jso.21788.CrossRefPubMed
36.
Li J, Yang L, Song L, Xiong H, Wang L, Yan X, Yuan J, Wu J, Li M: Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1. Oncogene. 2009, 28 (36): 3188-3196. 10.1038/onc.2009.171.CrossRefPubMed
37.
38.
Emdad L, Lee SG, Su ZZ, Jeon HY, Boukerche H, Sarkar D, Fisher PB: Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis. Proc Natl Acad Sci U S A. 2009, 106 (50): 21300-21305. 10.1073/pnas.0910936106.CrossRefPubMedPubMedCentral
39.
Ward A, Balwierz A, Zhang JD, Kublbeck M, Pawitan Y, Hielscher T, Wiemann S, Sahin O: Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer. Oncogene. 2013, 32 (9): 1173-1182. 10.1038/onc.2012.128.CrossRefPubMed
40.
Garcia-Garcia C, Ibrahim YH, Serra V, Calvo MT, Guzman M, Grueso J, Aura C, Perez J, Jessen K, Liu Y, Rommel C, Tabernero J, Baselga J, Scaltriti M: Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res. 2012, 18 (9): 2603-2612. 10.1158/1078-0432.CCR-11-2750.CrossRefPubMed
41.
Correia NC, Girio A, Antunes I, Martins LR, Barata JT: The multiple layers of non-genetic regulation of PTEN tumour suppressor activity. Eur J Cancer. 2014, 50 (1): 216-225. 10.1016/j.ejca.2013.08.017.CrossRefPubMed
42.
Song MS, Salmena L, Pandolfi PP: The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012, 13 (5): 283-296.PubMed
43.
Wang Q, Zhou Y, Wang X, Chung DH, Evers BM: Regulation of PTEN expression in intestinal epithelial cells by c-Jun NH2-terminal kinase activation and nuclear factor-kappaB inhibition. Cancer Res. 2007, 67 (16): 7773-7781. 10.1158/0008-5472.CAN-07-0187.CrossRefPubMedPubMedCentral
44.
Vasudevan KM, Gurumurthy S, Rangnekar VM: Suppression of PTEN expression by NF-kappa B prevents apoptosis. Mol Cell Biol. 2004, 24 (3): 1007-1021. 10.1128/MCB.24.3.1007-1021.2004.CrossRefPubMedPubMedCentral
45.
Chakrabarty A, Bhola NE, Sutton C, Ghosh R, Kuba MG, Dave B, Chang JC, Arteaga CL: Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors. Cancer Res. 2013, 73 (3): 1190-1200. 10.1158/0008-5472.CAN-12-2440.CrossRefPubMed
46.
Wu Y, Shang X, Sarkissyan M, Slamon D, Vadgama JV: FOXO1A is a target for HER2-overexpressing breast tumors. Cancer Res. 2010, 70 (13): 5475-5485. 10.1158/0008-5472.CAN-10-0176.CrossRefPubMedPubMedCentral
47.
Xu C, Kong X, Wang H, Zhang N, Kong X, Ding X, Li X, Yang Q: MTDH mediates estrogen-independent growth and tamoxifen resistance by down-regulating PTEN in MCF-7 breast cancer cells. Cell Physiol Biochem. 2014, 33 (5): 1557-1567. 10.1159/000358719.CrossRefPubMed
48.
Tanic N, Milovanovic Z, Tanic N, Dzodic R, Juranic Z, Susnjar S, Plesinac-Karapandzic V, Tatic S, Dramicanin T, Davidovic R, Dimitrijevic B: The impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen treatment in breast cancer patients. Cancer Biol Ther. 2012, 13 (12): 1165-1174. 10.4161/cbt.21346.CrossRefPubMedPubMedCentral
49.
Lindberg K, Helguero LA, Omoto Y, Gustafsson JA, Haldosen LA: Estrogen receptor beta represses Akt signaling in breast cancer cells via downregulation of HER2/HER3 and upregulation of PTEN: implications for tamoxifen sensitivity. Breast Cancer Res. 2011, 13 (2): R43-10.1186/bcr2865.CrossRefPubMedPubMedCentral
50.
Tural D, Serdengecti S, Demirelli F, Ozturk T, Ilvan S, Turna H, Ozguroglu M, Buyukunal E: Clinical significance of p95HER2 overexpression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies. Br J Cancer. 2014, 110 (12): 2996-10.1038/bjc.2014.314.CrossRefPubMedPubMedCentral
Metadata
Title
MTDH mediates trastuzumab resistance in HER2 positive breast cancer by decreasing PTEN expression through an NFκB-dependent pathway
Authors
Cheng Du
Xiaomin Yi
Wenchao Liu
Tao Han
Zhaozhe Liu
Zhenyu Ding
Zhendong Zheng
Ying Piao
Jianlin Yuan
Yaling Han
Manjiang Xie
Xiaodong Xie
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-869

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue

Research article

Differential regulation of MAGE-A1 promoter activity by BORIS and Sp1, both interacting with the TATA binding protein

Research article

Bortezomib and dexamethasone for multiple myeloma: higher AST and LDH levels associated with a worse prognosis on overall survival

Research article

Btbd7 contributes to reduced E-cadherin expression and predicts poor prognosis in non-small cell lung cancer

Research article

Evaluation of the walk-through inflatable colon as a colorectal cancer education tool: results from a pre and post research design

Research article

Overexpression of E2F1 in human gastric carcinoma is involved in anti-cancer drug resistance

Research article

Characterization of β2-microglobulin expression in different types of breast cancer
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