title: Genome-wide DNA methylation profiling reveals parity-associated hypermethylation of FOXA1.
abstract: Early pregnancy in women by the age of 20 is known to have a profound effect on reduction of lifelong breast cancer risk as compared to their nulliparous counterparts. Additional pregnancies further enhance the protection against breast cancer development. Nationwide trend of delayed pregnancy may contribute to the recently reported increase in the incidence of advanced breast cancer among young women in this country. The underlying mechanism for the parity-associated reduction of breast cancer risk is not clearly understood. The purpose of the current study is to use whole-genome DNA methylation profiling to explore a potential association between parity and epigenetic changes in breast tissue from women with early parity and nulliparity. Breast tissue was collected from age-matched cancer-free women with early parity (age < 20; n = 15) or nulliparity (n = 13). The methyl-CpG binding domain-based capture-sequencing technology was used for whole-genome DNA methylation profiling. Potential parity-associated hypermethylated genes were further verified by locus-specific pyrosequencing, using an expanded cohort of parous (n = 19) and nulliparous (n = 16) women that included the initial samples used in the global analysis. Our study identified six genes that are hypermethylated in the parous group (P < 0.05). Pyrosequencing confirmed parity-associated hypermethylation at multiple CpG islands of the FOXA1 gene, which encodes a pioneer factor that facilitates chromatin binding of estrogen receptor α. Our work identifies several potential methylation biomarkers for parity-associated breast cancer risk assessment. In addition, the results are consistent with the notion that parity-associated epigenetic silencing of FOXA1 contributes to long-term attenuation of the estrogenic impact on breast cancer development.
authors.affiliation: Department of Molecular Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Ghosh
authors.forename: Fei
authors.initials: F
authors.lastname: Gu
authors.forename: Chou-Miin
authors.initials: CM
authors.lastname: Wang
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Lin
authors.forename: Joseph
authors.initials: J
authors.lastname: Liu
authors.forename: Howard
authors.initials: H
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Ravdin
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Hu
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Huang
authors.forename: Rong
authors.initials: R
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016462:Mammaplasty; D042361:Mammary Glands, Human / Q000473:pathology / Q000601:surgery; D010298:Parity / Q000235:genetics*; D011247:Pregnancy; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118588:BCAR3 protein, human; C496499:FOXA1 protein, human; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D020662:Guanine Nucleotide Exchange Factors; D051541:Hepatocyte Nuclear Factor 3-alpha