Genome-wide DNA methylation profiling reveals parity-associated hypermethylation of FOXA1

Abstract

Purpose 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. Methods 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 (MBDCap)-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. Results Our study identified 6 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 (ERα). Conclusions 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.

FOXA1 hypermethylation: link between parity and ER-negative breast cancer in African American women?

“…This may be especially relevant for AA women, who are more likely to be parous [4] and not to breastfeed [5]. Previous studies have shown that reproductive factors are associated with DNA methylation differences in breast tissue, both normal and tumor [6, 7, 9]. Our data now indicate that DNA methylation of FOXA1 positively correlates with parity in AA women with ER− tumors, especially among those who did not breastfeed, providing some insight into potential etiologic mechanisms.…”

“…Reproductive events could influence divergence of luminal progenitor cells to ER+ and ER− populations through aberrant DNA methylation, altering expression of genes crucial to progenitor cell differentiation. Significantly, one recent study identified parity-associated hypermethylation of FOXA1 in normal breast tissue, suggesting that downregulation of this pioneer factor contributes to attenuation of ERα function, which may impact breast tumor development [9]. Thus, reproductive factors may affect breast cancer development through DNA methylation, and differential reproductive patterns between EA and AA women could influence the greater prevalence of ER− tumors in AAs through this mechanism.…”

Associations of reproductive breast cancer risk factors with breast tissue composition

“…Breast tissue changes during pregnancy have been suggested as possible reasons for the long-term protective effect on breast cancer risk [30]. The in uence of full term pregnancy on the breast tissue appears to be complex and some of the suggested mechanisms include changes in hormonal signaling in the breast, gene methylation and expression changes, long-term reduction in the levels of circulating hormones, and life-long reduction in the number of mammary stem cells [4,[31][32][33][34]. Previous studies also suggest that hormonal changes during pregnancy may also in uence stromal composition, but the evidence remains inconsistent [35][36][37].…”

Multiparity activates interferon pathways in peritoneal adipose tissue and decreases susceptibility to ovarian cancer metastasis in a murine allograft model

“…Additionally, it has been recently shown that methylome changes in tumor cells can lead to expression of endogenous retroviruses (ERVs), thereby activating type I IFN and resulting in growth inhibition of tumor cells [43]. Pregnancy is known to alter the methylome in breast tissue, and it is conceivable that the reproductive tract is similarly affected [44,45]. Future studies on IFN activation in response to pregnancies in the human ovarian surface epithelium and in peritoneal adipose tissue may provide insight into the parity-related effect on ovarian cancer reported in epidemiologic studies.…”