Associations of DNA methylation in breast tumour subtypes with parity and breastfeeding in a cohort of 1459 Black women: Implications for public health

Objective Having children reduces risk of breast cancer overall, but parity without breastfeeding, more prevalent among black women, increases risk of poor-prognosis oestrogen receptor negative (ER-) breast cancer. We investigated if relationships between parity, breastfeeding and ER subtypes result from epigenetic programming, potentially steering breast progenitor cells to a basal-like phenotype. Methods and analysis The Illumina MethylationEPIC platform was used to assess genome-wide methylation in formalin-fixed, paraffin-embedded tumours from 1459 Black women with breast cancer. Methylation was evaluated in relation to parity, breastfeeding and breast cancer subtypes in a case-only analysis, with methylation-gene expression pairs tested in a subset of cases. We then performed functional enrichment analysis for probes significantly associated with parity and breastfeeding. Results Among women who did not breastfeed (n=634), there were 500 significant (p<1e-5) differentially methylated loci (DML) by parity, compared with only five DMLs among women who had breastfed their children (n=568). One of the top DML genes was FOXA1, pivotal in governing the luminal lineage of progenitor cells, with a statistically significant interaction (p=0.04) for number of births and breastfeeding. Associations were strongest for ER- disease. Conclusion In this large study of Black women with breast cancer, we elucidated biological pathways for the observed associations between parity without breastfeeding and breast cancer subtypes, revealing distinct molecular alterations in breast DNA, particularly for ER- tumours. Black women in the USA tend to have more children and are less likely to breastfeed; their breast cancer risk may be reduced by societal systems that promote and support breastfeeding.