The pregnancy exposome and metabolome and risk for premenopausal breast cancer

The National Cancer Institute awarded Sequoia Foundation $589,761 for research investigating the pregnancy exposome and metabolome in relation to premenopausal breast cancer risk, under the Cancer Cause and Prevention Research program (CFDA 93.393), on August 11, 2026.

The project will conduct the first joint analysis of untargeted pregnancy exposome and metabolome data in connection with future premenopausal breast cancer risk. Using prenatal serum specimens from an established, population-based case-cohort of over 3,000 women pregnant between 2003 and 2019 in California—including 1,283 premenopausal breast cancer cases—the research will employ high-throughput, ultra-high resolution mass spectrometry and gas and liquid chromatography to quantify environmental chemical exposures and metabolic responses during pregnancy. The study addresses the hypothesis that chemical exposures during pregnancy, a critical window of hormone-induced breast differentiation and development, may initiate or promote breast carcinogenesis, with risk potentially modified by endogenous metabolic pathways. The research aims to identify early biologic signatures and potential predictive biomarkers of premenopausal breast cancer risk and to elucidate underlying mechanisms at the exposome scale, accounting for co-pollutant confounding and expansive chemical mixtures.

Work is performed in Berkeley, California. The period of performance runs through July 31, 2031. This is a Project Grant, an assistance type funding mechanism.

Abstract

Premenopausal breast cancer (pmbc), particularly when diagnosed postpartum, is increasing in incidence and is often more aggressive than breast cancer diagnosed later in life. Environmental chemical exposures may initiate or promote carcinogenesis in the breast and risk may be modified by endogenous metabolic pathways. Pregnant individuals are especially susceptible to effects of exogenous chemicals due to changes in substance metabolism, transport, and intake, which is critically important during hormone-induced breast differentiation and development. Pregnant people are exposed to a vast multiplicity of exogenous chemicals that may act synergistically on later disease risk, however little is known on how chemical exposures and metabolic responses during this critical window affect future pmbc risk. Research at the exposome scale, with the ability to comprehensively account for CO-pollutant confounding and investigate expansive chemical mixtures, may reveal disease relationships undetectable in single-pollutant or lower-dimensional approaches. Biologic reactions to these chemical exposures, along with numerous endogenous processes that modulate breast cancer risk are encoded in metabolic pathways, which change substantially with both pregnancy and menopause. Metabolomic profiling may yield identification of early biologic signatures of pmbc risk as well as insight into underlying mechanisms and the potential development of predictive biomarkers during pregnancy. This study will be the first to jointly analyze the untargeted pregnancy exposome and metabolome in relation to future pmbc risk. Using prenatal serum specimens from an established, population-based case-cohort of over 3,000 women pregnant in 2003-2019 in california (including 1,283 pmbc cases), high-throughput, ultra-high resolution mass spectrometry and gas and liquid chromatography will quantify more than 600 environmental chemicals and over 1,000 metabolites per sample. Advanced bioinformatics tools such as high-dimensional mixture modeling, network analysis, and multiomics data integration techniques will be used to characterize exposure and metabolic profiles, identify single and multiomic patterns associated with pmbc risk, and uncover mechanistic pathways linking environmental exposures to pmbc development. By quantifying both the exposome and metabolome we can determine pmbc risk in relation to complex patterns of real-world environmental exposures; metabolic biomarkers of endogenous biological risk; and, crucially, patterns of cross-omics interaction. Subtype-specific analyses will focus on more aggressive forms of early breast cancer, such as triple negative tumors and diagnoses within five or ten years of delivery. By capturing complex interactions between exposures and metabolic responses during pregnancy, this study has the potential to transform understanding of early-life breast cancer risk and guide novel prevention efforts. Findings from this work will fill critical gaps in breast cancer etiology, identify modifiable risk factors and early biologic markers, and lay groundwork for prevention or screening strategies tailored to pregnancy and the postpartum period.