Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes.
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.
Department of Pathology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
So Yeon
SY
Park
Hyeong Ju
HJ
Kwon
Yoomi
Y
Choi
Hee Eun
HE
Lee
Sung-Won
SW
Kim
Jee Hyun
JH
Kim
In Ah
IA
Kim
Namhee
N
Jung
Nam-Yun
NY
Cho
Gyeong Hoon
GH
Kang
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000080924:Aldehyde Dehydrogenase 1 Family; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D051927:CD24 Antigen / Q000032:analysis / Q000096:biosynthesis; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000096:biosynthesis; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics*; D050697:Retinal Dehydrogenase / Q000032:analysis / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D051927:CD24 Antigen; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase