Age- and Pregnancy-Associated DNA Methylation Changes in Mammary Epithelial Cells

Huh, Sung Jin; Clement, Kendell; Jee, David; Merlini, Alessandra; Choudhury, Sangita; Maruyama, Reo; Yoo, Ronnie; Chytil, Anna; Boyle, Patrick J.; Ran, F. Ann; Moses, Harold L.; Barcellos-Hoff, Mary Helen; Jackson-Grusby, Laurie; Meissner, Alexander; Polyák, Kornélia

doi:10.1016/j.stemcr.2014.12.009

Cited by 44 publications

(47 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…DNA methylation, a mitotically heritable epigenetic modification that occurs in temporally and spatially specific patterns throughout development, is affected by the milieu of hormonal changes that occur during breast development, pregnancy, and lactation in the human and mouse mammary gland [6–8]. DNA methylation changes could serve as markers to identify genes differentially regulated by reproductive factors which may contribute to the increased prevalence of ER− breast tumors in AA women.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Espinal

Buas

Wang

et al. 2017

Breast Cancer Res Treat

View full text Add to dashboard Cite

Background Reproductive factors, particularly parity, have differential effects on breast cancer risk according to estrogen receptor (ER) status, especially among African American (AA) women. One mechanism could be through DNA methylation, leading to altered expression levels of genes important in cell fate decisions. Methods Using the Illumina 450K BeadChip, we compared DNA methylation levels in paraffin-archived tumor samples from 383 AA and 350 European American (EA) women in the Women’s Circle of Health Study (WCHS). We combined 450K profiles with RNA-seq data and prioritized genes based on differential methylation by race, correlation between methylation and gene expression, and biological function. We measured tumor protein expression and assessed its relationship to DNA methylation. We evaluated associations between reproductive characteristics and DNA methylation using linear regression. Results 410 loci were differentially methylated by race, with the majority unique to ER− tumors. FOXA1 was hypermethylated in tumors from AA versus EA women with ER− cancer, and increased DNA methylation correlated with reduced RNA and protein expression. Importantly, parity was positively associated with FOXA1 methylation among AA women with ER− tumors (P = 0.022), as was number of births (P = 0.026), particularly among those who did not breastfeed (P = 0.008). These same relationships were not observed among EA women, although statistical power was more limited. Conclusions Methylation and expression of FOXA1 is likely impacted by parity and breastfeeding. Because FOXA1 regulates a luminal gene expression signature in progenitor cells and represses the basal phenotype, this could be a mechanism that links these reproductive exposures with ER− breast cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Espinal

Buas

Wang

et al. 2017

Breast Cancer Res Treat

View full text Add to dashboard Cite

show abstract

“…For example, methylation profiles from mammary epithelial cells are more similar to skin cells than blood cells, in keeping with the ectodermal origin of mammary and skin epithelial cells [25]. …”

Section: Dna Methylationmentioning

confidence: 94%

“…Pregnancy induces changes to the DNA methylome of both basal and luminal populations that persist throughout life [25, 26]. Genes involved in lactation and involution become hypomethylated in response to the pregnancy and are primed to respond robustly to subsequent pregnancies [26].…”

Section: Dna Methylationmentioning

confidence: 99%

Epigenomics of mammary gland development

et al. 2018

View full text Add to dashboard Cite

Differentiation of stem cells into highly specialised cells requires gene expression changes brought about by remodelling of the chromatin architecture. During this lineage-commitment process, the majority of DNA needs to be packaged into inactive heterochromatin, allowing only a subset of regulatory elements to remain open and functionally required genes to be expressed. Epigenetic mechanisms such as DNA methylation, post-translational modifications to histone tails, and nucleosome positioning all potentially contribute to the changes in higher order chromatin structure during differentiation. The mammary gland is a particularly useful model to study these complex epigenetic processes since the majority of its development is postnatal, the gland is easily accessible, and development occurs in a highly reproducible manner. Inappropriate epigenetic remodelling can also drive tumourigenesis; thus, insights into epigenetic remodelling during mammary gland development advance our understanding of breast cancer aetiology. We review the current literature surrounding DNA methylation and histone modifications in the developing mammary gland and its implications for breast cancer.

show abstract

“…Studies in mice and humans provide evidence that p27+ mammary epithelial cells with progenitor features decrease in number with pregnancy, and are present in high numbers in BRCA1 and BRCA2 germline mutation carriers (12,13). Evidence was presented that a subset of p27+ cells with progenitor features are hormone-responsive quiescent luminal progenitors with proliferative potential, and that their variation could relate to breast cancer risk (12).…”

Section: Introductionmentioning

confidence: 99%

Mathematical Modeling Links Pregnancy-Associated Changes and Breast Cancer Risk

et al. 2017

Self Cite

View full text Add to dashboard Cite

Recent debate has concentrated on the contribution of bad luck to cancer development. The tight correlation between the number of tissue-specific stem cell divisions and cancer risk of the same tissue suggests that bad luck has an important role to play in tumor development, but the full extent of this contribution remains an open question. Improved understanding of the interplay between extrinsic and intrinsic factors at the molecular level is one promising route to identifying the limits on extrinsic control of tumor initiation, which is highly relevant to cancer prevention. Here we use a simple mathematical model to show that recent data on the variation in numbers of breast epithelial cells with progenitor features due to pregnancy are sufficient to explain the known protective effect of full-term pregnancy in early adulthood for estrogen receptor positive (ER+) breast cancer later in life. Our work provides a mechanism for this previously ill-understood effect and illuminates the complex influence of extrinsic factors at the molecular level in breast cancer. These findings represent an important contribution to the ongoing research into the role of bad luck in human tumorigenesis.

show abstract

Age- and Pregnancy-Associated DNA Methylation Changes in Mammary Epithelial Cells

Cited by 44 publications

References 39 publications

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

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

Epigenomics of mammary gland development

Mathematical Modeling Links Pregnancy-Associated Changes and Breast Cancer Risk

Contact Info

Product

Resources

About