ABSTRACT: African-American (AA) women are more likely than other US groups to be diagnosed with
estrogen receptor negative (ER-) breast cancer, with poorer prognosis and higher mortality. Understanding the
biological mechanisms underlying ER- breast cancer in AA women and developing effective preventive
strategies represents a critical unmet need with major public health implications. We and others have shown
that risk of ER- breast cancer is increased among AA women who are parous and do not breastfeed; factors
that are more common among AA women, and may help to explain their higher incidence of ER- tumors. We
hypothesize that specific reproductive exposures result in epigenetic silencing of pro-luminal differentiation
genes via DNA methylation, leading to an expansion of aberrant, maturation-arrested luminal progenitor cells,
which can give rise to ER- cancers. Our previous data showed distinct differences in tumor DNA methylation
according to ER status. One strong candidate gene derived from these data is FOXA1, which promotes luminal
cell differentiation by positively regulating a luminal gene expression signature in progenitor cells and
repressing the basal cell phenotype. This gene was hyper-methylated in ER- versus ER+ tumors from AA
women, particularly in those who were parous and did not breastfeed. Consistent with inhibitory effects of
methylation on gene expression, FOXA1 protein levels were lower in ER- versus ER+ breast tumors, and lower
in ER- tumors from parous vs. nulliparous women. Supporting this hypothesis, we recently showed that
heterozygous deletion of Foxa1 in the mouse mammary gland results in a dramatic skewing of epithelial cell
populations toward luminal progenitors. Building on these preliminary results, we propose a comprehensive
genome-wide DNA methylation analysis of tumor samples from 1,621 AA women with breast cancer from the
Black Women's Health Study) and the Women's Circle of Health Study using the IIllumina EPIC 850K array.
Combining these profiles with existing 450K data from 383 AA cases after methylation imputation, we will
examine FOXA1 and differentially methylated loci (DMLs) that distinguish ER subgroups. With epidemiologic
data from these 2,004 AA cases, we will assess associations between reproductive risk factors and
methylation of FOXA1 and top DMLs, using weighted gene correlation network analysis and structural equation
modeling to evaluate complex relationships. We will evaluate the same relationships between parity,
breastfeeding and methylation in normal breast tissue donated by healthy AA volunteers to the Komen Tissue
Bank. Using mouse models, we will experimentally investigate if parity and breastfeeding influence the
methylation level of Foxa1 and other pro-luminal candidate genes, as well as relative proportions of distinct
mammary gland epithelial cell populations. This transdisciplinary, multi-pronged approach will enable us to
understand the etiology of aggressive breast cancer in AA women, facilitate the development of novel markers
for those at highest risk, and uncover promising molecular targets for precision prevention approaches.
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