Top

Published in:

01-06-2014 | Research Paper

Breast cancer nodal metastasis correlates with tumour and lymph node methylation profiles of Caveolin-1 and CXCR4

Authors: Leonidas Alevizos, Agapi Kataki, Anastasia Derventzi, Ilias Gomatos, Christos Loutraris, Georgia Gloustianou, Andreas Manouras, Manousos M. Konstadoulakis, George Zografos

Published in: Clinical & Experimental Metastasis | Issue 5/2014

Abstract

DNA methylation is the best characterised epigenetic change so far. However, its role in breast cancer metastasis has not as yet been elucidated. The aim of this study was to investigate the differences between the methylation profiles characterising primary tumours and their corresponding positive or negative for metastasis lymph nodes (LN) and correlate these with tumour metastatic potential. Methylation signatures of Caveolin-1, CXCR4, RAR-β, Cyclin D2 and Twist gene promoters were studied in 30 breast cancer primary lesions and their corresponding metastasis-free and tumour-infiltrated LN with Methylation-Specific PCR. CXCR4 and Caveolin-1 expression was further studied by immunohistochemistry. Tumours were typified by methylation of RAR-β and hypermethylation of Cyclin-D2 and Twist gene promoters. Tumour patterns were highly conserved in tumour-infiltrated LN. CXCR4 and Caveolin-1 promoter methylation patterns differentiated between node-negative and metastatic tumours. Nodal metastasis was associated with tumour and lymph node profiles of extended methylation of Caveolin-1 and lack of CXCR4 hypermethylation. Immunodetection studies verified CXCR4 and Caveolin-1 hypermethylation as gene silencing mechanism. Absence of Caveolin-1 expression in stromal cells associated with tumour aggressiveness while strong Caveolin-1 expression in tumour cells correlated with decreased 7-year disease-free survival. Methylation-mediated activation of CXCR4 and inactivation of Caveolin-1 was linked with nodal metastasis while intratumoral Caveolin-1 expression heterogeneity correlated with disease progression. This evidence contributes to the better understanding and, thereby, therapeutic management of breast cancer metastasis process.

Li Q, Chen H (2011) Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis. Epigenetics 6:849–852PubMedCrossRef

De Carvalho DD, Sharma S, You JS, Su SF, Taberlay PC, Kelly TK, Yang X, Liang G, Jones PA (2012) DNA methylation screening identifies driver epigenetic events of cancer cell survival. Cancer Cell 21:655–667PubMedCentralPubMedCrossRef

Sproul D, Kitchen RR, Nestor CE, Dixon JM, Sims AH, Harrison DJ, Ramsahoye BH, Meehan RR (2012) Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol 13:R84PubMedCentralPubMedCrossRef

Kulis M, Esteller M (2010) DNA methylation and cancer. Adv Genet 70:27–56

Hurst DR, Welch DR (2011) Metastasis suppressor genes at the interface between the environment and tumor cell growth. Int Rev Cell Mol Biol 286:107–180PubMedCentralPubMedCrossRef

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249PubMedCrossRef

Hill VK, Ricketts C, Bieche I, Vacher S, Gentle D, Lewis C, Maher ER, Latif F (2011) Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity. Cancer Res 71:2988–2999PubMedCrossRef

Barekati Z, Radpour R, Lu Q, Bitzer J, Zheng H, Toniolo P, Lenner P, Zhong XY (2012) Methylation signature of lymph node metastases in breast cancer patients. BMC Cancer 12:244PubMedCentralPubMedCrossRef

Feng W, Orlandi R, Zhao N, Carcangiu ML, Tagliabue E, Xu J, Bast RC Jr, Yu Y (2010) Tumor suppressor genes are frequently methylated in lymph node metastases of breast cancers. BMC Cancer 10:378PubMedCentralPubMedCrossRef

10.

Fackler MJ, McVeigh M, Mehrotra J, Blum MA, Lange J, Lapides A, Garrett E, Argani P, Sukumar S (2004) Quantitative multiplex methylation-specific PCR assay for the detection of promoter hypermethylation in multiple genes in breast cancer. Cancer Res 64:4442–4452PubMedCrossRef

11.

Borges S, Döppler H, Perez EA, Andorfer CA, Sun Z, Anastasiadis PZ, Thompson EA, Geiger XJ, Storz P (2013) Pharmacologic reversion of epigenetic silencing of the PRKD1 promoter blocks breast tumor cell invasion and metastasis. Breast Cancer Res 15:R66PubMedCrossRef

12.

Casey T, Bond J, Tighe S, Hunter T, Lintault L, Patel O, Eneman J, Crocker A, White J, Tessitore J, Stanley M, Harlow S, Weaver D, Muss H, Plaut K (2009) Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer. Breast Cancer Res Treat 114:47–62PubMedCrossRef

13.

Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298PubMedCrossRef

14.

Radpour R, Kohler C, Haghighi MM, Fan AX, Holzgreve W, Zhong XY (2009) Methylation profiles of 22 candidate genes in breast cancer using highthroughput MALDI-TOF mass array. Oncogene 28:2969–2978PubMedCrossRef

15.

Evron E, Dooley WC, Umbricht CB, Rosenthal D, Sacchi N, Gabrielson E, Soito AB, Hung DT, Ljung B, Davidson NE, Sukumar S (2001) Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR. Lancet 357:1335–1336PubMedCrossRef

16.

Tang D, Kryvenko ON, Mitrache N, Do KC, Jankowski M, Chitale DA, Trudeau S, Rundle A, Belinsky SA, Rybicki BA (2013) Methylation of the RARB gene increases prostate cancer risk in black Americans. J Urol 190:317–324PubMedCrossRef

17.

Zhou J, Tian Y, Li J, Lu B, Sun M, Zou Y, Kong R, Luo Y, Shi Y, Wang K, Ji G (2013) miR-206 is down-regulated in breast cancer and inhibits cell proliferation through the up-regulation of cyclinD2. Biochem Biophys Res Commun 433:207–212PubMedCrossRef

18.

Zhao M, Hu HG, Huang J, Zou Q, Wang J, Liu MQ, Zhao Y, Li GZ, Xue S, Wu ZS (2013) Expression and correlation of Twist and gelatinases in breast cancer. Exp Ther Med 6:97–100PubMedCentralPubMed

19.

Widschwendter M, Berger J, Hermann M, Müller HM, Amberger A, Zeschnigk M, Widschwendter A, Abendstein B, Zeimet AG, Daxenbichler G, Marth C (2000) Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. J Natl Cancer Inst 92:826–832PubMedCrossRef

20.

Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH, Hannon GJ (1999) Twist is a potential oncogene that inhibits apoptosis. Genes Dev 13:2207–2217PubMedCentralPubMedCrossRef

21.

Ramos EA, Grochoski M, Braun-Prado K, Seniski GG, Cavalli IJ, Ribeiro EM, Camargo AA, Costa FF, Klassen G (2011) Epigenetic changes of CXCR4 and its ligand CXCL12 as prognostic factors for sporadic breast cancer. PLoS One 6:29461CrossRef

22.

Carraway HE, Wang S, Blackford A, Guo M, Powers P, Jeter S, Davidson NE, Argani P, Terrell K, Herman JG, Lange JR (2009) Promoter hypermethylation in sentinel lymph nodes as a marker for breast cancer recurrence. Breast Cancer Res Treat 114:315–325PubMedCentralPubMedCrossRef

23.

Mori T, Kim J, Yamano T, Takeuchi H, Huang S, Umetani N, Koyanagi K, Hoon DS (2005) Epigenetic Up-regulation of C-C chemokine receptor 7 and C-X-C chemokine receptor 4 expression in melanoma cells. Cancer Res 65:1800–1807PubMedCrossRef

24.

Sato N, Matsubayashi H, Fukushima N, Goggins M (2005) The chemokine receptor CXCR4 is regulated by DNA methylation in pancreatic cancer. Cancer Biol Ther 4:70–76PubMedCrossRef

25.

Furusato B, Mohamed A, Uhlen M, Rhim JS (2010) CXCR4 and cancer. Pathol Int 60:497–505PubMedCrossRef

26.

Chen ST, Lin SY, Yeh KT (2004) Mutational, epigenetic and expressional analyses of caveolin-1 gene in breast cancers. Int J Mol Med 14:577–582PubMed

27.

Lin SY, Yeh KT, Chen WT, Chen HC, Chen ST, Chang JG (2004) Promoter CpG methylation of caveolin-1 in sporadic colorectal cancer. Anticancer Res 24:1645–1650PubMed

28.

Hehlgans S, Cordes N (2011) Caveolin-1: an essential modulator of cancer cell radio and chemoresistance. Am J Cancer Res 1:521–530PubMedCentralPubMed

29.

Sloan EK, Stanley KL, Anderson RL (2004) Caveolin-1 inhibits breast cancer growth and metastasis. Oncogene 23:7893–7897PubMedCrossRef

30.

Simpkins SA, Hanby AM, Holliday DL, Speirs V (2012) Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. J Pathol 227:490–498PubMedCrossRef

31.

Sherif ZA, Sultan AS (2012) Divergent control of Cav-1 expression in non-cancerous Li-Fraumeni syndrome and human cancer cell lines. Cancer Biol Ther 14:29–38PubMedCrossRef

32.

Qian N, Ueno T, Kawaguchi-Sakita N et al (2011) Prognostic significance of tumour/stromal caveolin-1 expression in breast cancer patients. Cancer Sci 102:1590–1596PubMedCrossRef

33.

Fiucci G, Ravid D, Reich R, Liscovitch M (2002) Caveolin-1 inhibits anchorage independent growth, anoikis and invasiveness in MCF-7 human breast cancer cells. Oncogene 21:2365–2375PubMedCrossRef

34.

Sotgia F, Del Galdo F, Casimiro MC, Bonuccelli G, Mercier I, Whitaker-Menezes D, Daumer KM, Zhou J, Wang C et al (2008) Caveolin-1^−/− null mammary stromal fibroblasts share characteristics with human breast cancer-associated fibroblasts. Am J Pathol 174:746–761CrossRef

35.

Cat B, Stuhlmann D, Steinbrenner H, Alili L, Holtkotter O, Sies H, Brenneisen P (2006) Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species. J Cell Sci 119:2727–2738PubMedCrossRef

36.

Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C, Pavlides S, Martinez-Cantarin MP et al (2010) Autophagy in cancer associated fibroblasts promotes tumor cell survival: role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment. Cell Cycle 9:3515–3533PubMedCentralPubMedCrossRef

Title: Breast cancer nodal metastasis correlates with tumour and lymph node methylation profiles of Caveolin-1 and CXCR4
Authors: Leonidas Alevizos
Agapi Kataki
Anastasia Derventzi
Ilias Gomatos
Christos Loutraris
Georgia Gloustianou
Andreas Manouras
Manousos M. Konstadoulakis
George Zografos
Publication date: 01-06-2014
Publisher: Springer Netherlands
Published in: Clinical & Experimental Metastasis / Issue 5/2014
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-014-9645-6

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

Please log in to get access to this content

Other articles of this Issue 5/2014

Augmented expression of urokinase plasminogen activator and extracellular matrix proteins associates with multiple myeloma progression

Mechanisms of resistance to imatinib mesylate in KIT-positive metastatic uveal melanoma

Decreased expression of RASSF1A and up-regulation of RASSF1C is associated with esophageal squamous cell carcinoma

Genetics of breast cancer bone metastasis: a sequential multistep pattern

Is insulin-like growth factor binding protein 2 associated with metastasis in lung cancer?

Molecular response of the axillary lymph node microenvironment to metastatic colonization

Keynote webinar | Spotlight on antibody–drug conjugates in cancer