Pattern of expression of genes linked to epigenetic silencing in human breast cancer

Kailas Munot, Sandra M Bell, Sally Lane, Kieran Horgan, Andrew M Hanby, Valerie Speirs

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Epigenetic mechanisms such as DNA methylation are now recognized to play an important role in neoplasia. The aim of this study is to relate the pattern of expression of multiple cancer genes known to undergo epigenetic inactivation by promoter hypermethylation in breast cancer with histologic and outcome data. We used immunohistochemistry to study expression of the tumor suppressor gene p16, estrogen receptor (ER) alpha, ERbeta, progesterone receptor (PR), and the DNA repair gene MGMT (O6 -methylguanine-DNA methyltransferase) in a panel of 200 breast cancers. Methylation-specific polymerase chain reaction was used to confirm MGMT promoter methylation. Loss of expression of MGMT, ERalpha, ERbeta, PR, and p16 was observed in 19%, 24%, 13%, 40%, and 50% of cases, respectively. A significant correlation was seen between grade III tumor and loss of expression of ERalpha, ERbeta, PR (all P < .0001), and MGMT (P = .04), whereas loss of expression of p16 was associated with grades I and II tumors (P < .001). Cases that expressed 3 or less of the 5 proteins studied had significantly reduced survival (P = .0016). Methylation-specific polymerase chain reaction in a subset of 20 cancers showed DNA methylation associated with the loss of MGMT expression (P < .001). In conclusion, there is silencing of several key genes in breast cancer affecting molecular pathways involved in cell immortalization, DNA repair, and hormonal regulation, and this correlates significantly with risk of cancer-specific death. This expression profile could be linked to epigenetic events, and if so, these pathways have potential as targets for therapeutic strategies based on reversal of epigenetic silencing.

Original languageEnglish
Pages (from-to)989-99
Number of pages11
JournalHuman Pathology
Volume37
Issue number8
DOIs
Publication statusPublished - Aug 2006

Fingerprint

Epigenomics
Estrogen Receptor beta
Estrogen Receptor alpha
Breast Neoplasms
Gene Expression
Methyltransferases
Progesterone Receptors
DNA
Methylation
DNA Methylation
Neoplasms
DNA Repair
Polymerase Chain Reaction
Neoplasm Genes
Tumor Suppressor Genes
Genes
Immunohistochemistry
O-(6)-methylguanine
Survival
Proteins

Keywords

  • Adenocarcinoma
  • Biomarkers, Tumor
  • Breast Neoplasms
  • DNA Methylation
  • DNA, Neoplasm
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Immunoenzyme Techniques
  • Lymph Nodes
  • Lymphatic Metastasis
  • Mammary Glands, Human
  • Middle Aged
  • Neoplasm Staging
  • O(6)-Methylguanine-DNA Methyltransferase
  • Polymerase Chain Reaction
  • Survival Rate
  • United Kingdom
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Pattern of expression of genes linked to epigenetic silencing in human breast cancer. / Munot, Kailas; Bell, Sandra M; Lane, Sally; Horgan, Kieran; Hanby, Andrew M; Speirs, Valerie.

In: Human Pathology, Vol. 37, No. 8, 08.2006, p. 989-99.

Research output: Contribution to journalArticle

Munot, Kailas ; Bell, Sandra M ; Lane, Sally ; Horgan, Kieran ; Hanby, Andrew M ; Speirs, Valerie. / Pattern of expression of genes linked to epigenetic silencing in human breast cancer. In: Human Pathology. 2006 ; Vol. 37, No. 8. pp. 989-99.
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AU - Bell, Sandra M

AU - Lane, Sally

AU - Horgan, Kieran

AU - Hanby, Andrew M

AU - Speirs, Valerie

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AB - Epigenetic mechanisms such as DNA methylation are now recognized to play an important role in neoplasia. The aim of this study is to relate the pattern of expression of multiple cancer genes known to undergo epigenetic inactivation by promoter hypermethylation in breast cancer with histologic and outcome data. We used immunohistochemistry to study expression of the tumor suppressor gene p16, estrogen receptor (ER) alpha, ERbeta, progesterone receptor (PR), and the DNA repair gene MGMT (O6 -methylguanine-DNA methyltransferase) in a panel of 200 breast cancers. Methylation-specific polymerase chain reaction was used to confirm MGMT promoter methylation. Loss of expression of MGMT, ERalpha, ERbeta, PR, and p16 was observed in 19%, 24%, 13%, 40%, and 50% of cases, respectively. A significant correlation was seen between grade III tumor and loss of expression of ERalpha, ERbeta, PR (all P < .0001), and MGMT (P = .04), whereas loss of expression of p16 was associated with grades I and II tumors (P < .001). Cases that expressed 3 or less of the 5 proteins studied had significantly reduced survival (P = .0016). Methylation-specific polymerase chain reaction in a subset of 20 cancers showed DNA methylation associated with the loss of MGMT expression (P < .001). In conclusion, there is silencing of several key genes in breast cancer affecting molecular pathways involved in cell immortalization, DNA repair, and hormonal regulation, and this correlates significantly with risk of cancer-specific death. This expression profile could be linked to epigenetic events, and if so, these pathways have potential as targets for therapeutic strategies based on reversal of epigenetic silencing.

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KW - Biomarkers, Tumor

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KW - DNA Methylation

KW - DNA, Neoplasm

KW - Epigenesis, Genetic

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Gene Silencing

KW - Humans

KW - Immunoenzyme Techniques

KW - Lymph Nodes

KW - Lymphatic Metastasis

KW - Mammary Glands, Human

KW - Middle Aged

KW - Neoplasm Staging

KW - O(6)-Methylguanine-DNA Methyltransferase

KW - Polymerase Chain Reaction

KW - Survival Rate

KW - United Kingdom

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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DO - 10.1016/j.humpath.2006.04.013

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VL - 37

SP - 989

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JO - Human Pathology

JF - Human Pathology

SN - 0046-8177

IS - 8

ER -