Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes

So Yeon Park, Hyeong Ju Kwon, Yoomi Choi, Hee Eun Lee, Sung Won Kim, Jee Hyun Kim, In Ah Kim, Namhee Jung, Nam Yun Cho, Gyeong Hoon Kang

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. This study was designed to evaluate the promoter CpG island methylation of 15 genes in relation to breast cancer subtype, and to investigate whether the patterns of CpG island methylation in each subtype are associated with their cancer stem cell phenotype represented by CD44 +CD24-and ALDH1 expression. We performed MethyLight analysis of the methylation status of 15 promoter CpG island loci involved in breast cancer progression (APC, DLEC1, GRIN2B, GSTP1, HOXA1, HOXA10, IGF2, MT1G, RARB, RASSF1A, RUNX3, SCGB3A1, SFRP1, SFRP4, and TMEFF2) and determined cancer stem cell phenotype by CD44 +CD24-and ALDH1 immunohistochemistry in 36 luminal A, 33 luminal B, 30 luminal-HER2, 40 HER2 enriched, and 40 basal-like subtypes of breast cancer. The number of CpG island loci methylated differed significantly between subtypes, and was highest in the luminal-HER2 subtype and lowest in the basal-like subtype. Methylation frequencies and levels in 12 of the 15 genes differed significantly between subtypes, and the basal-like subtype had significantly lower methylation frequencies and levels in nine of the genes than the other subtypes. CD44 +CD24-and ALDH1 putative stem cell populations were most enriched in the basal-like subtype. Methylation of promoter CpG islands was significantly lower in CD44 +CD24-cell (+) tumors than in CD44 +CD24-cell (-) tumors, even within the basal-like subtype. ALDH1 (+) tumors were also less methylated than ALDH1 (-) tumors. Our findings showed that promoter CpG island methylation was different in relation to breast cancer subtype and stem cell phenotype of tumor, suggesting that breast cancers have distinct patterns of CpG island methylation according to molecular subtypes and these are associated with different stem cell phenotypes of the tumor.

Original languageEnglish
Pages (from-to)185-196
Number of pages12
JournalModern Pathology
Volume25
Issue number2
DOIs
Publication statusPublished - 2012 Feb 1

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CpG Islands
Methylation
Stem Cells
Breast Neoplasms
Phenotype
Neoplastic Stem Cells
DNA Methylation
Neoplasms
Genes
Immunohistochemistry
aldehyde dehydrogenase 1

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Park, So Yeon ; Kwon, Hyeong Ju ; Choi, Yoomi ; Lee, Hee Eun ; Kim, Sung Won ; Kim, Jee Hyun ; Kim, In Ah ; Jung, Namhee ; Cho, Nam Yun ; Kang, Gyeong Hoon. / Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes. In: Modern Pathology. 2012 ; Vol. 25, No. 2. pp. 185-196.
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abstract = "Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. This study was designed to evaluate the promoter CpG island methylation of 15 genes in relation to breast cancer subtype, and to investigate whether the patterns of CpG island methylation in each subtype are associated with their cancer stem cell phenotype represented by CD44 +CD24-and ALDH1 expression. We performed MethyLight analysis of the methylation status of 15 promoter CpG island loci involved in breast cancer progression (APC, DLEC1, GRIN2B, GSTP1, HOXA1, HOXA10, IGF2, MT1G, RARB, RASSF1A, RUNX3, SCGB3A1, SFRP1, SFRP4, and TMEFF2) and determined cancer stem cell phenotype by CD44 +CD24-and ALDH1 immunohistochemistry in 36 luminal A, 33 luminal B, 30 luminal-HER2, 40 HER2 enriched, and 40 basal-like subtypes of breast cancer. The number of CpG island loci methylated differed significantly between subtypes, and was highest in the luminal-HER2 subtype and lowest in the basal-like subtype. Methylation frequencies and levels in 12 of the 15 genes differed significantly between subtypes, and the basal-like subtype had significantly lower methylation frequencies and levels in nine of the genes than the other subtypes. CD44 +CD24-and ALDH1 putative stem cell populations were most enriched in the basal-like subtype. Methylation of promoter CpG islands was significantly lower in CD44 +CD24-cell (+) tumors than in CD44 +CD24-cell (-) tumors, even within the basal-like subtype. ALDH1 (+) tumors were also less methylated than ALDH1 (-) tumors. Our findings showed that promoter CpG island methylation was different in relation to breast cancer subtype and stem cell phenotype of tumor, suggesting that breast cancers have distinct patterns of CpG island methylation according to molecular subtypes and these are associated with different stem cell phenotypes of the tumor.",
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Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes. / Park, So Yeon; Kwon, Hyeong Ju; Choi, Yoomi; Lee, Hee Eun; Kim, Sung Won; Kim, Jee Hyun; Kim, In Ah; Jung, Namhee; Cho, Nam Yun; Kang, Gyeong Hoon.

In: Modern Pathology, Vol. 25, No. 2, 01.02.2012, p. 185-196.

Research output: Contribution to journalArticle

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T1 - Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes

AU - Park, So Yeon

AU - Kwon, Hyeong Ju

AU - Choi, Yoomi

AU - Lee, Hee Eun

AU - Kim, Sung Won

AU - Kim, Jee Hyun

AU - Kim, In Ah

AU - Jung, Namhee

AU - Cho, Nam Yun

AU - Kang, Gyeong Hoon

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