Pharmacologic Unmasking of Epigenetically Silenced Genes in Breast Cancer

Purpose: Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of various cancers including breast cancer. Many epigenetically inactivated genes involved in breast cancer development remain to be identified. Therefore, in thi...

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Bibliographic Details
Published in:Clinical cancer research 2009-02, Vol.15 (4), p.1184-1191
Main Authors: Ostrow, Kimberly Laskie, Park, Hannah Lui, Hoque, Mohammad Obaidul, Kim, Myoung Sook, Liu, Junwei, Argani, Pedram, Westra, William, Van Criekinge, Wim, Sidransky, David
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic agents
Biological and medical sciences
breast
Breast Neoplasms - genetics
Cell Line, Tumor
DNA Methylation
Epigenesis, Genetic
epigenetics
Female
Gene Silencing
Gynecology. Andrology. Obstetrics
Humans
Kinesin - genetics
Mammary gland diseases
Medical sciences
Membrane Transport Proteins - genetics
methylation
Middle Aged
Myelin and Lymphocyte-Associated Proteolipid Proteins
Myelin Proteins - genetics
Nerve Growth Factors - genetics
Oligonucleotide Array Sequence Analysis
Pharmacology. Drug treatments
Promoter Regions, Genetic
Proteolipids - genetics
Tacrolimus Binding Proteins - genetics
Tumors
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Summary:Purpose: Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of various cancers including breast cancer. Many epigenetically inactivated genes involved in breast cancer development remain to be identified. Therefore, in this study we used a pharmacologic unmasking approach in breast cancer cell lines with 5-aza-2′-deoxycytidine (5-aza-dC) followed by microarray expression analysis to identify epigenetically inactivated genes in breast cancer. Experimental Design: Breast cancer cell lines were treated with 5-aza-dC followed by microarray analysis to identify epigenetically inactivated genes in breast cancer. We then used bisulfite DNA sequencing, conventional methylation-specific PCR, and quantitative fluorogenic real-time methylation-specific PCR to confirm cancer-specific methylation in novel genes. Results: Forty-nine genes were up-regulated in breast cancer cells lines after 5-aza-dC treatment, as determined by microarray analysis. Five genes ( MAL, FKBP4, VGF, OGDHL , and KIF1A ) showed cancer-specific methylation in breast tissues. Methylation of at least two was found at high frequency only in breast cancers (40 of 40) as compared with normal breast tissue (0 of 10; P < 0.0001, Fisher's exact test). Conclusions: This study identified new cancer-specific methylated genes to help elucidate the biology of breast cancer and as candidate diagnostic markers for the disease.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-08-1304