title: CXCL12 and ADAM23 hypermethylation are associated with advanced breast cancers.
abstract: More than 25% of the patients with breast cancer (BC) develop metastatic disease. In the present study, we investigated the relationship between DNA methylation levels in genes regulating cell growth, invasiveness, and metastasis and advanced BCs and evaluated the clinical utility of methylation profiles for detecting metastatic potential. Pyrosequencing was used to quantify methylation levels in 11 cancer-associated genes in primary tumors (PTs), lymph node metastases (LNMs), plasma (PL), and blood cells from 206 patients with invasive BC. Protein expression was evaluated using immunohistochemistry. PTs showed hypermethylation of A isoform of the RAS-association domain family 1 (RASSF1A), adenomatous polyposis coli (APC), chemokine C-X-C motif ligand 12 (CXCL12), and disintegrin and metalloprotease domain 23 (ADAM23) (means 38.98%, 24.84%, 12.04%, and 10.01%, respectively). Positive correlations were identified between methylations in PTs and LNMs, but not between PL and PTs. The cumulative methylation of PTs and LNMs manifested similar spectrums of methylated genes that indicate the maintaining of aberrant methylation during breast tumorigenesis. Significantly increased methylation levels in RASSF1A, APC, CXCL12, and ADAM23 were found in estrogen receptor (ER) positive BCs in comparison with ER negative cases. Regarding these results, the evaluation of DNA methylation could be more informative in testing of patients with ER positive BC. The risk for LNMs development and higher proliferation of cancer cells measured through Ki-67 expression was increased by hypermethylation of CXCL12 and ADAM23, respectively. Therefore, the quantification of CXCL12 and ADAM23 methylation could be useful for the prediction of advanced stage of BC.
authors.affiliation: Department of Genetics, Cancer Research Institute of SAS, Bratislava, Slovak Republic. Electronic address: ivanafrid@gmail.com.
authors.forename: Ivana
authors.initials: I
authors.lastname: Fridrichova
authors.affiliation: Department of Genetics, Cancer Research Institute of SAS, Bratislava, Slovak Republic.
authors.forename: Bozena
authors.initials: B
authors.lastname: Smolkova
authors.affiliation: Department of Genetics, Cancer Research Institute of SAS, Bratislava, Slovak Republic.
authors.forename: Viera
authors.initials: V
authors.lastname: Kajabova
authors.affiliation: Department of Genetics, Cancer Research Institute of SAS, Bratislava, Slovak Republic.
authors.forename: Iveta
authors.initials: I
authors.lastname: Zmetakova
authors.affiliation: Department of Genetics, Cancer Research Institute of SAS, Bratislava, Slovak Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Krivulcik
authors.affiliation: Faculty of Medicine, Second Department of Oncology, Comenius University, National Cancer Institute, Bratislava, Slovak Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Mego
authors.affiliation: Faculty of Medicine, Institute of Pathological Anatomy, Comenius University, University Hospital, Bratislava, Slovak Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Cierna
authors.affiliation: Department of Surgical Oncology, National Cancer Institute, Bratislava, Slovak Republic.
authors.forename: Marian
authors.initials: M
authors.lastname: Karaba
authors.affiliation: Department of Surgical Oncology, National Cancer Institute, Bratislava, Slovak Republic.
authors.forename: Juraj
authors.initials: J
authors.lastname: Benca
authors.affiliation: Department of Surgical Oncology, National Cancer Institute, Bratislava, Slovak Republic.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pindak
authors.affiliation: Department of Plastic, Aesthetic and Reconstructive Surgery, University Hospital, Bratislava, Slovak Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Bohac
authors.affiliation: Faculty of Medicine, Institute of Medical Biology, Genetics and Clinical Genetics, Comenius University, University Hospital, Bratislava, Slovak Republic.
authors.forename: Vanda
authors.initials: V
authors.lastname: Repiska
authors.affiliation: Faculty of Medicine, Institute of Pathological Anatomy, Comenius University, University Hospital, Bratislava, Slovak Republic; Pathological-Anatomical Workplace, Health Care Surveillance Authority, Bratislava, Slovak Republic.
authors.forename: Ludovit
authors.initials: L
authors.lastname: Danihel
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D054377:Chemokine CXCL12 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008875:Middle Aged
chemical_list: D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D051722:ADAM Proteins; C114633:ADAM23 protein, human