MAPK Genes Interact with Diet and Lifestyle Factors to Alter Risk of Breast Cancer: The Breast Cancer Health Disparities Study

Abstract

Mitogen-activated protein kinases (MAPK) are integration points for multiple biochemical signals. We evaluated 13 MAPK genes with breast cancer risk and determined if diet and lifestyle factors mediated risk. Data from three population-based case-control studies conducted in Southwestern United States, California, and Mexico included 4183 controls and 3592 cases. Percent Indigenous American (IA) ancestry was determined from 104 Ancestry Informative Markers. The adaptive rank truncated product (ARTP) was used to determine the significance of each gene and the pathway with breast cancer risk, by menopausal status, genetic ancestry level, and ER/PR strata. MAP3K9 was associated with breast cancer overall (PARTP=0.02) with strongest association among women with the highest IA ancestry (PARTP=0.04). Several SNPs in MAP3K9 were associated with ER+/PR+ tumors and interacted with dietary oxidative balance score (DOBS), dietary folate, body mass index (BMI), alcohol consumption, cigarette smoking, and a history of diabetes. DUSP4 and MAPK8 interacted with calories to alter breast cancer risk; MAPK1 interacted with DOBS, dietary fiber, folate and BMI; MAP3K2 interacted with dietary fat; and MAPK14 interacted with dietary folate and BMI. The patterns of association across diet and lifestyle factors with similar biological properties for the same SNPs within genes provide support for associations.

Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns

“…Some are relevant to NTDs, the indication for maternal folic acid supplementation, and others to distinct developmental conditions that have not been previously associated with maternal folate levels. Additional genes we identified have been implicated in conditions where there is some concern about possible adverse effects of higher folate levels, such as breast cancer progression 16 . Due to the large number of genes significantly differentially methylated in relation to folate ( Supplementary Data 1 and 2 ), we focus this discussion primarily on genes with two or more CpGs at genome-wide significance after FDR correction ( P BH <0.05) where at least one CpG is within the gene ( Table 2 ).…”

Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with lifestyle factors on postmenopausal breast cancer risk

“…A previous study [26] showed an interaction between MAPK1 genetic variants and obesity and related lifestyle factors on breast cancer. Consistent with the results of that study, we found that carriers of the genetic variant in MAPK1 rs2298432 had decreased breast cancer risk only in non-viscerally obese women, indicating that IGF/IR axis cellular pathway-related carcinogenesis in this variant intermingles with visceral adiposity.…”

“…The PI3K/Akt pathway leads to metabolic activity, including glucose uptake and decreased apoptosis, and the MAPK pathway leads to mitogenic activity [54]; both are main signaling cascades in controlling cellular process promoting carcinogenesis [55,56]. PIK3R1, AKT1/2, and MAPK1 genes are the key components of these pathways [26,55,[57][58][59], but the studies of their genetic variants in relation to cancer have been limited [12,[24][25][26][27].…”

“…Ten genes (Tables S1.1-6) were selected based on the biological significance of their gene products, or whether epidemiologic and/or experimental data support an association between the gene and the levels of IGF and insulin or between the gene and risk of cancer [12,[15][16][17][18][19][20][21][22][24][25][26][27]. For each gene, HTSNP2 (http://www-gene.cimr.cam.ac.uk/ clayton/software/stata) searched all possible subsets of SNPs that best captured the full haplotype information.…”

“…In addition, the genetic alterations of IGF-I/IR signaling pathways lead to altered gene expression and protein function and are found in more than 70% of breast cancers [23]. Thus, the genetic variants that are related to IGF-I/IR signaling pathways are plausibly associated with increased risk of breast cancer, although population-based studies to examine these relationships have been limited [12,[24][25][26][27].…”