title: Tissue specific DNA methylation in normal human breast epithelium and in breast cancer.
abstract: Cancer is a heterogeneous and tissue-specific disease. Thus, the tissue of origin reflects on the natural history of the disease and dictates the therapeutic approach. It is suggested that tissue differentiation, mediated mostly by epigenetic modifications, could guide tissue-specific susceptibility and protective mechanisms against cancer. Here we studied breast specific methylation in purified normal epithelium and its reflection in breast cancers. We established genome wide methylation profiles of various normal epithelial tissues and identified 110 genes that were differentially methylated in normal breast epithelium. A number of these genes also showed methylation alterations in breast cancers. We elaborated on one of them, TRIM29 (ATDC), and showed that its promoter was hypo-methylated in normal breast epithelium and heavily methylated in other normal epithelial tissues. Moreover, in breast carcinomas methylation increased and expression decreased whereas the reverse was noted for multiple other carcinomas. Interestingly, TRIM29 regulation in breast tumors clustered according to the PAM50 classification. Thus, it was repressed in the estrogen receptor positive tumors, particularly in the more proliferative luminal B subtype. This goes in line with previous reports indicating tumor suppressive activity of TRIM29 in estrogen receptor positive luminal breast cells in contrast to oncogenic function in pancreatic and lung cancers. Overall, these findings emphasize the linkage between breast specific epigenetic regulation and tissue specificity of cancer.
authors.affiliation: Department of Oncology, Assaf Harofeh Medical Center, Affiliated with Tel Aviv University, Zerifin, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Avraham
authors.affiliation: Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Sean Soonweng
authors.initials: SS
authors.lastname: Cho
authors.affiliation: Department of Oncology, Assaf Harofeh Medical Center, Affiliated with Tel Aviv University, Zerifin, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Uhlmann
authors.affiliation: Department of Pathology, Assaf Harofeh Medical Center, Affiliated with Tel Aviv University, Zerifin, Israel.
authors.forename: Mia Leonov
authors.initials: ML
authors.lastname: Polak
authors.affiliation: Department of Pathology, Assaf Harofeh Medical Center, Affiliated with Tel Aviv University, Zerifin, Israel.
authors.forename: Judith
authors.initials: J
authors.lastname: Sandbank
authors.affiliation: Department of Surgery, Assaf Harofeh Medical Center, Affiliated with Tel Aviv University, Zerifin, Israel.
authors.forename: Tami
authors.initials: T
authors.lastname: Karni
authors.affiliation: Department of Surgery, Assaf Harofeh Medical Center, Affiliated with Tel Aviv University, Zerifin, Israel.
authors.forename: Itzhak
authors.initials: I
authors.lastname: Pappo
authors.affiliation: Department of Genecology, Assaf Harofeh Medical Center, Affiliated with Tel Aviv University, Zerifin, Israel.
authors.forename: Ruvit
authors.initials: R
authors.lastname: Halperin
authors.affiliation: Department of Genecology, Assaf Harofeh Medical Center, Affiliated with Tel Aviv University, Zerifin, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Vaknin
authors.affiliation: Department of Oncology, Assaf Harofeh Medical Center, Affiliated with Tel Aviv University, Zerifin, Israel.
authors.forename: Avishay
authors.initials: A
authors.lastname: Sella
authors.affiliation: Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.affiliation: Department of Oncology, Assaf Harofeh Medical Center, Affiliated with Tel Aviv University, Zerifin, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Evron
mesh_terms: D001940:Breast / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C087296:TRIM29 protein, human; D014157:Transcription Factors