Epigenetic silencing of DSC3 is a common event in human breast cancer.

Marc M. Oshiro, Christina J. Kim, Ryan J. Wozniak, Damian J. Junk, José L. Muñoz-Rodríguez, Jeanne A. Burr, Matthew Fitzgerald, Sangita C. Pawar, Anne E Cress, Frederick E. Domann, Bernard W Futscher

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Abstract

INTRODUCTION: Desmocollin 3 (DSC3) is a member of the cadherin superfamily of calcium-dependent cell adhesion molecules and a principle component of desmosomes. Desmosomal proteins such as DSC3 are integral to the maintenance of tissue architecture and the loss of these components leads to a lack of adhesion and a gain of cellular mobility. DSC3 expression is down-regulated in breast cancer cell lines and primary breast tumors; however, the loss of DSC3 is not due to gene deletion or gross rearrangement of the gene. In this study, we examined the prevalence of epigenetic silencing of DSC3 gene expression in primary breast tumor specimens. METHODS: We used bisulfite genomic sequencing to analyze the methylation state of the DSC3 promoter region from 32 primary breast tumor specimens. We also used a quantitative real-time RT-PCR approach, and analyzed all breast tumor specimens for DSC3 expression. Finally, in addition to bisulfite sequencing and RT-PCR, we used an in vivo nuclease accessibility assay to determine the chromatin architecture of the CpG island region from DSC3-negative breast cancer cells lines. RESULTS: DSC3 expression was downregulated in 23 of 32 (72%) breast cancer specimens comprising: 22 invasive ductal carcinomas, 7 invasive lobular breast carcinomas, 2 invasive ductal carcinomas that metastasized to the lymph node, and a mucoid ductal carcinoma. Of the 23 specimens showing a loss of DSC3 expression, 13 (56%) were associated with cytosine hypermethylation of the promoter region. Furthermore, DSC3 expression is limited to cells of epithelial origin and its expression of mRNA and protein is lost in a high proportion of breast tumor cell lines (79%). Lastly, DNA hypermethylation of the DSC3 promoter is highly correlated with a closed chromatin structure. CONCLUSION: These results indicate that the loss of DSC3 expression is a common event in primary breast tumor specimens, and that DSC3 gene silencing in breast tumors is frequently linked to aberrant cytosine methylation and concomitant changes in chromatin structure.

Original languageEnglish (US)
JournalBreast Cancer Research
Volume7
Issue number5
StatePublished - 2005

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Desmocollins
Epigenomics
Breast Neoplasms
Ductal Carcinoma
Chromatin
Cytosine
Genetic Promoter Regions
Methylation
Lobular Carcinoma
Cell Line
Desmosomes
CpG Islands
Gene Rearrangement

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Oshiro, M. M., Kim, C. J., Wozniak, R. J., Junk, D. J., Muñoz-Rodríguez, J. L., Burr, J. A., ... Futscher, B. W. (2005). Epigenetic silencing of DSC3 is a common event in human breast cancer. Breast Cancer Research, 7(5).

Epigenetic silencing of DSC3 is a common event in human breast cancer. / Oshiro, Marc M.; Kim, Christina J.; Wozniak, Ryan J.; Junk, Damian J.; Muñoz-Rodríguez, José L.; Burr, Jeanne A.; Fitzgerald, Matthew; Pawar, Sangita C.; Cress, Anne E; Domann, Frederick E.; Futscher, Bernard W.

In: Breast Cancer Research, Vol. 7, No. 5, 2005.

Research output: Contribution to journalArticle

Oshiro, MM, Kim, CJ, Wozniak, RJ, Junk, DJ, Muñoz-Rodríguez, JL, Burr, JA, Fitzgerald, M, Pawar, SC, Cress, AE, Domann, FE & Futscher, BW 2005, 'Epigenetic silencing of DSC3 is a common event in human breast cancer.', Breast Cancer Research, vol. 7, no. 5.
Oshiro MM, Kim CJ, Wozniak RJ, Junk DJ, Muñoz-Rodríguez JL, Burr JA et al. Epigenetic silencing of DSC3 is a common event in human breast cancer. Breast Cancer Research. 2005;7(5).
Oshiro, Marc M. ; Kim, Christina J. ; Wozniak, Ryan J. ; Junk, Damian J. ; Muñoz-Rodríguez, José L. ; Burr, Jeanne A. ; Fitzgerald, Matthew ; Pawar, Sangita C. ; Cress, Anne E ; Domann, Frederick E. ; Futscher, Bernard W. / Epigenetic silencing of DSC3 is a common event in human breast cancer. In: Breast Cancer Research. 2005 ; Vol. 7, No. 5.
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title = "Epigenetic silencing of DSC3 is a common event in human breast cancer.",
abstract = "INTRODUCTION: Desmocollin 3 (DSC3) is a member of the cadherin superfamily of calcium-dependent cell adhesion molecules and a principle component of desmosomes. Desmosomal proteins such as DSC3 are integral to the maintenance of tissue architecture and the loss of these components leads to a lack of adhesion and a gain of cellular mobility. DSC3 expression is down-regulated in breast cancer cell lines and primary breast tumors; however, the loss of DSC3 is not due to gene deletion or gross rearrangement of the gene. In this study, we examined the prevalence of epigenetic silencing of DSC3 gene expression in primary breast tumor specimens. METHODS: We used bisulfite genomic sequencing to analyze the methylation state of the DSC3 promoter region from 32 primary breast tumor specimens. We also used a quantitative real-time RT-PCR approach, and analyzed all breast tumor specimens for DSC3 expression. Finally, in addition to bisulfite sequencing and RT-PCR, we used an in vivo nuclease accessibility assay to determine the chromatin architecture of the CpG island region from DSC3-negative breast cancer cells lines. RESULTS: DSC3 expression was downregulated in 23 of 32 (72{\%}) breast cancer specimens comprising: 22 invasive ductal carcinomas, 7 invasive lobular breast carcinomas, 2 invasive ductal carcinomas that metastasized to the lymph node, and a mucoid ductal carcinoma. Of the 23 specimens showing a loss of DSC3 expression, 13 (56{\%}) were associated with cytosine hypermethylation of the promoter region. Furthermore, DSC3 expression is limited to cells of epithelial origin and its expression of mRNA and protein is lost in a high proportion of breast tumor cell lines (79{\%}). Lastly, DNA hypermethylation of the DSC3 promoter is highly correlated with a closed chromatin structure. CONCLUSION: These results indicate that the loss of DSC3 expression is a common event in primary breast tumor specimens, and that DSC3 gene silencing in breast tumors is frequently linked to aberrant cytosine methylation and concomitant changes in chromatin structure.",
author = "Oshiro, {Marc M.} and Kim, {Christina J.} and Wozniak, {Ryan J.} and Junk, {Damian J.} and Mu{\~n}oz-Rodr{\'i}guez, {Jos{\'e} L.} and Burr, {Jeanne A.} and Matthew Fitzgerald and Pawar, {Sangita C.} and Cress, {Anne E} and Domann, {Frederick E.} and Futscher, {Bernard W}",
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AU - Oshiro, Marc M.

AU - Kim, Christina J.

AU - Wozniak, Ryan J.

AU - Junk, Damian J.

AU - Muñoz-Rodríguez, José L.

AU - Burr, Jeanne A.

AU - Fitzgerald, Matthew

AU - Pawar, Sangita C.

AU - Cress, Anne E

AU - Domann, Frederick E.

AU - Futscher, Bernard W

PY - 2005

Y1 - 2005

N2 - INTRODUCTION: Desmocollin 3 (DSC3) is a member of the cadherin superfamily of calcium-dependent cell adhesion molecules and a principle component of desmosomes. Desmosomal proteins such as DSC3 are integral to the maintenance of tissue architecture and the loss of these components leads to a lack of adhesion and a gain of cellular mobility. DSC3 expression is down-regulated in breast cancer cell lines and primary breast tumors; however, the loss of DSC3 is not due to gene deletion or gross rearrangement of the gene. In this study, we examined the prevalence of epigenetic silencing of DSC3 gene expression in primary breast tumor specimens. METHODS: We used bisulfite genomic sequencing to analyze the methylation state of the DSC3 promoter region from 32 primary breast tumor specimens. We also used a quantitative real-time RT-PCR approach, and analyzed all breast tumor specimens for DSC3 expression. Finally, in addition to bisulfite sequencing and RT-PCR, we used an in vivo nuclease accessibility assay to determine the chromatin architecture of the CpG island region from DSC3-negative breast cancer cells lines. RESULTS: DSC3 expression was downregulated in 23 of 32 (72%) breast cancer specimens comprising: 22 invasive ductal carcinomas, 7 invasive lobular breast carcinomas, 2 invasive ductal carcinomas that metastasized to the lymph node, and a mucoid ductal carcinoma. Of the 23 specimens showing a loss of DSC3 expression, 13 (56%) were associated with cytosine hypermethylation of the promoter region. Furthermore, DSC3 expression is limited to cells of epithelial origin and its expression of mRNA and protein is lost in a high proportion of breast tumor cell lines (79%). Lastly, DNA hypermethylation of the DSC3 promoter is highly correlated with a closed chromatin structure. CONCLUSION: These results indicate that the loss of DSC3 expression is a common event in primary breast tumor specimens, and that DSC3 gene silencing in breast tumors is frequently linked to aberrant cytosine methylation and concomitant changes in chromatin structure.

AB - INTRODUCTION: Desmocollin 3 (DSC3) is a member of the cadherin superfamily of calcium-dependent cell adhesion molecules and a principle component of desmosomes. Desmosomal proteins such as DSC3 are integral to the maintenance of tissue architecture and the loss of these components leads to a lack of adhesion and a gain of cellular mobility. DSC3 expression is down-regulated in breast cancer cell lines and primary breast tumors; however, the loss of DSC3 is not due to gene deletion or gross rearrangement of the gene. In this study, we examined the prevalence of epigenetic silencing of DSC3 gene expression in primary breast tumor specimens. METHODS: We used bisulfite genomic sequencing to analyze the methylation state of the DSC3 promoter region from 32 primary breast tumor specimens. We also used a quantitative real-time RT-PCR approach, and analyzed all breast tumor specimens for DSC3 expression. Finally, in addition to bisulfite sequencing and RT-PCR, we used an in vivo nuclease accessibility assay to determine the chromatin architecture of the CpG island region from DSC3-negative breast cancer cells lines. RESULTS: DSC3 expression was downregulated in 23 of 32 (72%) breast cancer specimens comprising: 22 invasive ductal carcinomas, 7 invasive lobular breast carcinomas, 2 invasive ductal carcinomas that metastasized to the lymph node, and a mucoid ductal carcinoma. Of the 23 specimens showing a loss of DSC3 expression, 13 (56%) were associated with cytosine hypermethylation of the promoter region. Furthermore, DSC3 expression is limited to cells of epithelial origin and its expression of mRNA and protein is lost in a high proportion of breast tumor cell lines (79%). Lastly, DNA hypermethylation of the DSC3 promoter is highly correlated with a closed chromatin structure. CONCLUSION: These results indicate that the loss of DSC3 expression is a common event in primary breast tumor specimens, and that DSC3 gene silencing in breast tumors is frequently linked to aberrant cytosine methylation and concomitant changes in chromatin structure.

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