Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model

George P Skliris, Kailas Munot, Sandra M Bell, Pauline J Carder, Sally Lane, Kieran Horgan, Mark R J Lansdown, Alicia T Parkes, Andrew M Hanby, Alexander F Markham, Valerie Speirs

Research output: Contribution to journalArticle

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Abstract

To gain insights into the possible role of oestrogen receptor (ER) beta in breast carcinogenesis, immunohistochemical analysis of ER beta was performed on 512 breast specimens encompassing normal (n = 138), pure ductal carcinoma in situ (n = 16), invasive cancers (n = 319), lymph node metastases (n = 31), and recurrences (n = 8). Real-time polymerase chain reaction (PCR) was used to investigate the methylation status of the ER beta gene in the ER beta negative breast cancer cell lines SkBr3 and MDA-MB-435. A gradual reduction in, but not a complete loss of, ER beta expression was observed during the transition from normal and pre-invasive lesions to invasive cancers, where ER beta was lost in 21% of cases. This was more pronounced in invasive ductal than in lobular carcinomas, a significantly higher proportion of which were ER beta-positive (74% compared with 91%, respectively, p = 0.0004). Examination of paired primary cancers with their axillary lymph node metastases showed that if ER beta was present in the primary tumour, it persisted in the metastasis. Treatment of ER beta-negative cell lines with DNA methyl transferase inhibitors restored ER beta expression, providing experimental evidence that silencing of ER beta in breast carcinomas could be due to promoter hypermethylation. These results suggest that loss of ER beta expression is one of the hallmarks of breast carcinogenesis and that it may be a reversible process involving methylation.

Original languageEnglish
Pages (from-to)213-20
Number of pages8
JournalThe Journal of pathology
Volume201
Issue number2
DOIs
Publication statusPublished - Oct 2003

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Estrogen Receptor beta
Transferases
Breast Neoplasms
Cell Line
Breast
DNA
Neoplasm Metastasis
Methylation
Neoplasms
Carcinogenesis
Lymph Nodes
Lobular Carcinoma
Carcinoma, Intraductal, Noninfiltrating
Real-Time Polymerase Chain Reaction
Recurrence
Genes

Keywords

  • Age Factors
  • Azacitidine
  • Breast Neoplasms
  • Carcinoma, Ductal, Breast
  • Carcinoma, Lobular
  • Cervical Intraepithelial Neoplasia
  • Chi-Square Distribution
  • DNA Methylation
  • DNA Modification Methylases
  • Estrogen Receptor beta
  • Female
  • Gene Silencing
  • Humans
  • Immunohistochemistry
  • Lymphatic Metastasis
  • Neoplasm Recurrence, Local
  • Receptors, Estrogen
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Comparative Study
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. / Skliris, George P; Munot, Kailas; Bell, Sandra M; Carder, Pauline J; Lane, Sally; Horgan, Kieran; Lansdown, Mark R J; Parkes, Alicia T; Hanby, Andrew M; Markham, Alexander F; Speirs, Valerie.

In: The Journal of pathology, Vol. 201, No. 2, 10.2003, p. 213-20.

Research output: Contribution to journalArticle

Skliris, GP, Munot, K, Bell, SM, Carder, PJ, Lane, S, Horgan, K, Lansdown, MRJ, Parkes, AT, Hanby, AM, Markham, AF & Speirs, V 2003, 'Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model', The Journal of pathology, vol. 201, no. 2, pp. 213-20. https://doi.org/10.1002/path.1436
Skliris, George P ; Munot, Kailas ; Bell, Sandra M ; Carder, Pauline J ; Lane, Sally ; Horgan, Kieran ; Lansdown, Mark R J ; Parkes, Alicia T ; Hanby, Andrew M ; Markham, Alexander F ; Speirs, Valerie. / Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. In: The Journal of pathology. 2003 ; Vol. 201, No. 2. pp. 213-20.
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abstract = "To gain insights into the possible role of oestrogen receptor (ER) beta in breast carcinogenesis, immunohistochemical analysis of ER beta was performed on 512 breast specimens encompassing normal (n = 138), pure ductal carcinoma in situ (n = 16), invasive cancers (n = 319), lymph node metastases (n = 31), and recurrences (n = 8). Real-time polymerase chain reaction (PCR) was used to investigate the methylation status of the ER beta gene in the ER beta negative breast cancer cell lines SkBr3 and MDA-MB-435. A gradual reduction in, but not a complete loss of, ER beta expression was observed during the transition from normal and pre-invasive lesions to invasive cancers, where ER beta was lost in 21{\%} of cases. This was more pronounced in invasive ductal than in lobular carcinomas, a significantly higher proportion of which were ER beta-positive (74{\%} compared with 91{\%}, respectively, p = 0.0004). Examination of paired primary cancers with their axillary lymph node metastases showed that if ER beta was present in the primary tumour, it persisted in the metastasis. Treatment of ER beta-negative cell lines with DNA methyl transferase inhibitors restored ER beta expression, providing experimental evidence that silencing of ER beta in breast carcinomas could be due to promoter hypermethylation. These results suggest that loss of ER beta expression is one of the hallmarks of breast carcinogenesis and that it may be a reversible process involving methylation.",
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AU - Munot, Kailas

AU - Bell, Sandra M

AU - Carder, Pauline J

AU - Lane, Sally

AU - Horgan, Kieran

AU - Lansdown, Mark R J

AU - Parkes, Alicia T

AU - Hanby, Andrew M

AU - Markham, Alexander F

AU - Speirs, Valerie

N1 - Copyright 2003 John Wiley & Sons, Ltd.

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N2 - To gain insights into the possible role of oestrogen receptor (ER) beta in breast carcinogenesis, immunohistochemical analysis of ER beta was performed on 512 breast specimens encompassing normal (n = 138), pure ductal carcinoma in situ (n = 16), invasive cancers (n = 319), lymph node metastases (n = 31), and recurrences (n = 8). Real-time polymerase chain reaction (PCR) was used to investigate the methylation status of the ER beta gene in the ER beta negative breast cancer cell lines SkBr3 and MDA-MB-435. A gradual reduction in, but not a complete loss of, ER beta expression was observed during the transition from normal and pre-invasive lesions to invasive cancers, where ER beta was lost in 21% of cases. This was more pronounced in invasive ductal than in lobular carcinomas, a significantly higher proportion of which were ER beta-positive (74% compared with 91%, respectively, p = 0.0004). Examination of paired primary cancers with their axillary lymph node metastases showed that if ER beta was present in the primary tumour, it persisted in the metastasis. Treatment of ER beta-negative cell lines with DNA methyl transferase inhibitors restored ER beta expression, providing experimental evidence that silencing of ER beta in breast carcinomas could be due to promoter hypermethylation. These results suggest that loss of ER beta expression is one of the hallmarks of breast carcinogenesis and that it may be a reversible process involving methylation.

AB - To gain insights into the possible role of oestrogen receptor (ER) beta in breast carcinogenesis, immunohistochemical analysis of ER beta was performed on 512 breast specimens encompassing normal (n = 138), pure ductal carcinoma in situ (n = 16), invasive cancers (n = 319), lymph node metastases (n = 31), and recurrences (n = 8). Real-time polymerase chain reaction (PCR) was used to investigate the methylation status of the ER beta gene in the ER beta negative breast cancer cell lines SkBr3 and MDA-MB-435. A gradual reduction in, but not a complete loss of, ER beta expression was observed during the transition from normal and pre-invasive lesions to invasive cancers, where ER beta was lost in 21% of cases. This was more pronounced in invasive ductal than in lobular carcinomas, a significantly higher proportion of which were ER beta-positive (74% compared with 91%, respectively, p = 0.0004). Examination of paired primary cancers with their axillary lymph node metastases showed that if ER beta was present in the primary tumour, it persisted in the metastasis. Treatment of ER beta-negative cell lines with DNA methyl transferase inhibitors restored ER beta expression, providing experimental evidence that silencing of ER beta in breast carcinomas could be due to promoter hypermethylation. These results suggest that loss of ER beta expression is one of the hallmarks of breast carcinogenesis and that it may be a reversible process involving methylation.

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KW - Chi-Square Distribution

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KW - Female

KW - Gene Silencing

KW - Humans

KW - Immunohistochemistry

KW - Lymphatic Metastasis

KW - Neoplasm Recurrence, Local

KW - Receptors, Estrogen

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Tumor Cells, Cultured

KW - Comparative Study

KW - Journal Article

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

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VL - 201

SP - 213

EP - 220

JO - The Journal of pathology

JF - The Journal of pathology

SN - 0022-3417

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ER -