AS749 - Role of the insulinemic dietary pattern in lipids and insulin/MTOR signaling: impact on the racial disparity in breast cancer

Investigator Names and Contact Information

Fred K. Tabung (Fred.Tabung@osumc.edu) Ting-Yuan David Cheng (ting-yuan.cheng@osumc.edu)

Introduction/Intent

Abstract Diet-related hyperinsulinemia measured using the Empirical Dietary Index for Hyperinsulinemia (EDIH) score is 3-fold higher in Black compared to White women. A high EDIH diet is also associated with aggressive (HR-negative) breast cancer (BCa) subtypes and may contribute to the observed Black-White disparity in BCamortality. Racial differences are also evident in breast tumor tissue, where insulin is a potent activator of thePI3K/PTEN/MTOR pathway, and MTOR overactivation is more likely to be observed in breast tumors fromBlack than White women. In this proposed study, we will test the central hypothesis that high EDIH increasesinsulin/IR and lipid signaling, resulting in chronic activation of the MTOR pathway that is more pronounced inBlack compared to White women. We will use data on diet and biospecimens in the Women’s Health Initiative’sLife and Longevity After Cancer (LILAC) survivorship cohort, comprising 2,400 BCa cases with tumor tissue(5.5% Black) and 5,934 controls (7.0% Black). In addition, we will validate findings in a sample of 2,615 womenincluding 715 (80% Black) cases and 1,900 controls (64% Black) with existing data in the Women’s Circle ofHealth Study. Three specific aims are proposed: Aim 1: Identify how racial disparities modify the influence ofEDIH on BCa incidence and mortality by EDIH-related plasma lipidomic profiles; Aim 2: Define how EDIHdietary profiles impact breast tumor molecular profiles to drive the racial disparity in BCa incidence andmortality. Aim 3: Determine the extent to which genetic variation in the MTOR pathway is associated with lipidprofiles and drives disparities in BCa between Black and White women. We will request 250 L plasma sampleat WHI baseline for lipidomic assay, 10 tissue microarray (TMA) sections, and 1.5ug DNA at 50 ng/uL forMTOR pathway genes. Our findings will inform the development of racially targeted and scalable dietaryinterventions to mitigate aberrant lipid and PI3K/PTEN/MTOR signaling associated with high EDIH and BCarisk as well as progression in racially diverse women.

The following three specific aims are proposed: Aim 1: Identify how racial disparities modify the influence of EDIH on BCa incidence and mortality by EDIH-related plasma lipidomic profiles. Our working hypothesis is that higher (vs lower) EDIH leads to more unfavorable plasma lipid profiles among Black women and predisposes them to a greater risk of developing aggressive (HR-negative) disease, compared to White women. Aim 2: Define how EDIH dietary profiles impact breast tumor molecular profiles to drive the racial disparity in BCa incidence and mortality. Our working hypothesis is that higher (vs. lower) EDIH predisposes to a greater risk of tumors with higher protein expression of IR, IGF1R, p-AKT, p-MTOR, pS6K, greater proliferative activity (Ki-67) and more frequent PTEN loss, especially in Black than in White women. Aim 3: Determine the extent to which genetic variation in the MTOR pathway is associated with lipid profiles and drives the disparity in BCa among Black and White women. Our working hypothesis is that a higher proportion of women with high polygenic risk for dysfunctional MTOR pathway also have high EDIH/unfavorable plasma lipid profiles and are predominantly Black than White, with consequent higher burden of aggressive BCa.