Top

Published in:

01-02-2015 | Research Paper

Epigenetic variations in breast cancer progression to lymph node metastasis

Authors: Guillermo Urrutia, Sergio Laurito, Diego M. Marzese, Francisco Gago, Javier Orozco, Olga Tello, Teresita Branham, Emanuel M. Campoy, María Roqué

Published in: Clinical & Experimental Metastasis | Issue 2/2015

Abstract

Breast cancer is a heterogeneous disease characterized by the accumulation of genetic and epigenetic alterations that contribute to the development of regional and distant metastases. Lymph node metastasis (LNM) status is the single most important prognostic factor. Metastatic cancer cells share common molecular alterations with those of the primary tumor, but in addition, they develop distinct changes that allow the cancer to progress. There is an urgent need for molecular studies which focus on identifying genomic and epigenomic markers that can predict the progression to metastasis. The objective of this study was to identify epigenetic similarities and differences between paired primary breast tumor (PBT) and LNM. We employed Methylation-Specific-MLPA (Multiplex ligation-dependent probe amplification) to assess the methylation status of 33 cancer-related genes in a cohort of 50 paired PBT and LNM specimens. We found that the methylation index, which represents the degree of aberrantly methylated genes in a specimen, was maintained during the progression to LNM. However, some genes presented differential methylation profiles. Interestingly, PAX6 presented a significant negative correlation between paired PBT and LNM (p = 0.03), which indicated a switch from methylated to unmethylated status in the progression from PBT to LNM. We further identified that the methylation status of PAX6 on the identified CpG site functionally affected the expression of PAX6 at the mRNA level. Our study unraveled significant epigenetic changes during the progression from PBT to LNM, which may contribute to improved prognosis, prediction and therapeutic management of metastatic breast cancer patients.

Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer Statistics. J Clin 64:9–29CrossRef

Senkus E, Kyriakides S, Penault-Llorea F, Poortmans P, Thompson A, Zackrisson S, Cardoso F, ESMO Guidelines Working Group (2013) Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow up. Ann Oncol 24:7–23CrossRef

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cel 144:646–674CrossRef

Taback B, Hoon DS (2004) Circulating nucleic acids in plasma and serum: past, present and future. Curr Opin Mol Ther 6:273–278PubMed

Rykova EY (2008) Methylation-based analysis of circulating DNA for breast tumor screening. Ann NY Acad Sci 1137(1):232–235PubMedCrossRef

Esteller M, Fraga MF, Guo M, Garcia-Foncillas J, Hedenfalk I, Godwin AK, Trojan J, Vaurs-Barriere C, Bignon YJ, Ramus S, Benitez J, Caldes T, Akiyama Y, Yuasa Y, Launonen V, Canal MJ, Rodriguez R, Capella G, Peinado MA, Borg A, Aaltonen LA, Ponder BA, Baylin SB, Herman JG (2001) DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 10:3001–3007PubMedCrossRef

Moelans CB, Verschuur-Maes AH, van Diest PJ (2011) Frequent promoter hypermethylation of BRCA2, CDH13, MSH6, PAX5, PAX6 and WT1 in ductal carcinoma in situ and invasive breast cancer. J Pathol 225:222–231PubMedCrossRef

Lindner DJ, Wu Y, Haney R, Jacobs BS, Fruehauf JP, Tuthill R, Borden EC (2013) Thrombospondin-1 expression in melanoma is blocked by methylation and targeted reversal by 5-Aza-deoxycytidine suppresses angiogenesis. Matrix Biol 32:123–132PubMedCentralPubMedCrossRef

Widschwendter M (2001) Epigenetic downregulation of the retinoic acid receptor-beta2 gene in breast cancer. J Mammary Gland Biol Neoplas 6(2):193–201CrossRef

10.

Bergman Y, Cedar H (2013) DNA methylation dynamics in health and disease. Nat Struct Mol Biol 20:274–281PubMedCrossRef

11.

Flanagan JM, Cocciardi S, Waddell N, Johnstone CN, Marsh A, Henderson S, Simpson P, Da Silva L, Khanna K, Lakhani S, Boshoff C, Chenevix-Trench G (2010) DNA methylome of familial breast cancer identifies distinct profiles defined by mutation status. Am J Hum Genet 86:420–433PubMedCentralPubMedCrossRef

12.

Marzese DM, Hoon DS, Chong KK, Gago FE, Orozco JI, Tello OM, Vargas-Roig LM, Roque M (2012) DNA methylation index and methylation profile of invasive ductal breast tumors. J Mol Diagn 14:613–622PubMedCrossRef

13.

Twelves D, Nerurkar A, Osin P, Dexter T, Ward A, Gui GP, Isacke CM (2013) DNA promoter hypermethylation profiles in breast duct fluid. Breast Cancer Res Treat 139:341–350PubMedCrossRef

14.

Sighoko D, Liu J, Hou N, Gustafson P, Huo D (2014) Discordance in hormone receptor status among primary, metastatic, and second primary breast cancers: biological difference or misclassification? Oncologist 19:592–601PubMedCrossRef

15.

Yao ZX, Lu LJ, Wang RJ, Jin LB, Liu SC, Li HY, Ren GS, Wu KN, Wang DL, Kong LQ (2014) Discordance and clinical significance of ER, PR, and HER2 status between primary breast cancer and synchronous axillary lymph node metastasis. Med Oncol 31:1–7

16.

Aurilio G, Disalvatore D, Pruneri G, Bagnardi V, Viale G, Curigliano G, Adamoli L, Munzone E, Sciandivasci A, De Vita F, Goldhirsch A, Nole F (2014) A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J. Cancer 50:277–289PubMedCrossRef

17.

Ibrahim T, Farolfi A, Scarpi E, Mercatali L, Medri L, Ricci M, Nanni O, Serra L, Amadori D (2013) Hormonal receptor, human epidermal growth factor receptor-2, and Ki67 discordance between primary breast cancer and paired metastases: clinical impact. Oncology 84:150–157PubMedCrossRef

18.

Marzese DM, Gago FE, Vargas-Roig LM, Roque M (2010) Simultaneous analysis of the methylation profile of 26 cancer related regions in invasive breast carcinomas by MS-MLPA and drMS-MLPA. Mol Cell Probes 24:271–280PubMedCrossRef

19.

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

20.

Metge BJ, Frost AR, King JA, Dyess DL, Welch DR, Samant RS, Shevde LA (2008) Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer. Clin Exp Metastasis 25:753–763PubMedCentralPubMedCrossRef

21.

Rivenbark AG, Livasy CA, Boyd CE, Keppler D, Coleman WB (2007) Methylation-dependent silencing of CST6 in primary human breast tumors and metastatic lesions. Exp Mol Pathol 83:188–197PubMedCentralPubMedCrossRef

22.

Alevizos L, Kataki A, Derventzi A, Gomatos I, Loutraris C, Gloustianou G, Manouras A, Konstadoulakis M, Zografos G (2014) Breast cancer nodal metastasis correlates with tumor and lymph node methylation profiles of Caveolin-1 and CXCR4. Clin Exp Metastasis 31:511–520PubMedCrossRef

23.

Skryabin NA, Tolmacheva EN, Lebedev IN, Zavyalova MV, Slonimskaya EM, Cherdyntseva NV (2013) Dynamics of aberrant methylation of futional groups of genes in progression of breast. Cancer Mol Biol 47:302–310

24.

Walther C, Gruss P (1991) Pax-6, a murine paired box gene, is expressed in the developing CNS. Development 113:1435–1449PubMed

25.

Huang BS, Luo QZ, Han Y, Li XB, Cao LJ, Wu LX (2013) microRNA-223 promotes the growth and invasion of glioblastoma cells by targeting tumor suppressor PAX6. Oncol Rep 30:2263–2269PubMed

26.

Li Y, Li Y, Liu Y, Xie P, Li F, Li G (2014) PAX6, a novel target of microRNA-7, promotes cellular proliferation and invasion in human colorectal cancer cells. Dig Dis Sci 59:598–606PubMedCrossRef

27.

Zhao X, Yue W, Zhang L, Ma L, Jia W, Qian Z, Zhang C, Wang Y (2014) Downregulation of PAX6 by shRNA inhibits proliferation and cell cycle progression of human non-small cell lung cancer cell lines. PLoS One 9:e85738PubMedCentralPubMedCrossRef

28.

Wang J, Wang X, Wu G, Hou D, Hu Q (2013) MiR-365b-3p, down-regulated in retinoblastoma, regulates cell cycle progression and apoptosis of human retinoblastoma cells by targeting PAX6. FEBS Lett 587:1779–1786PubMedCrossRef

Title: Epigenetic variations in breast cancer progression to lymph node metastasis
Authors: Guillermo Urrutia
Sergio Laurito
Diego M. Marzese
Francisco Gago
Javier Orozco
Olga Tello
Teresita Branham
Emanuel M. Campoy
María Roqué
Publication date: 01-02-2015
Publisher: Springer Netherlands
Published in: Clinical & Experimental Metastasis / Issue 2/2015
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-015-9695-4

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 2/2015

Prognostic significance of histology after resection of brain metastases and whole brain radiotherapy in non-small cell lung cancer (NSCLC)

Bladder metastasis from renal cell carcinoma: retrospective analysis of 65 reported cases

Pattern of metastasis and outcome in patients with breast cancer

Lenalidomide and cyclophosphamide immunoregulation in patients with metastatic, castration-resistant prostate cancer

HES1 promotes metastasis and predicts poor survival in patients with colorectal cancer

HER2 and β-catenin protein location: importance in the prognosis of breast cancer patients and their correlation when breast cancer cells suffer stressful situations

Keynote webinar | Spotlight on antibody–drug conjugates in cancer