Mammographic dense breast tissue, characterized by an increase in the proliferation of epithelial cells and stromal fibrosis is considered a significant breast cancer risk factor. There is evidence that genetic susceptibility accounts for approximately 60% of the variation in mammographic density. We conducted a cross-sectional study to evaluate the effect of epidemiological factors on the relationship between genetic factors and percent density. We assessed mamographic percent density using a validated computer-assisted thresholding method among 396 cancer-free women at MD Anderson Cancer Center. Participant’s DNA was genotyped for 107 single nucleotide polymorphisms (SNPs) in candidate genes associated with breast cancer risk as part of a case-control study assessing genetic factors associated with breast cancer risk. Detailed information on breast cancer risk factors was collected. We used the recursive partitioning approach to identify epidemiological predictors as well as SNPs in candidate genes potentially associated with percent density. Among all participants, epidemiological factors associated with increased percent density included premenopausal status (p<.001), low body mass index (p<.001) and hormone replacement therapy use (HRT) (p<.001). When stratified by menopausal status, SNPs in p53 (rs1042522) (p=.004) and ADP-ribosyltransferase (rs1136410) (p=.02) were associated with increased percent density among postmenopausal women and SNPs in OGG1 (rs1052133) (p=.01), CYP1B1 (rs1056836) (p=.03), MSH6 (rs3136229) (p=.03), HER2 (rs1058808) (p=.02), PGR (rs10895068) (p=.04), PHB (rs2233667) (p=.01) and p53 (rs1042522 (p=.03) were associated with increased percent density in premenopausal women. Genetic determinants of percent mammographic density differ according to menopausal status. A more comprehensive understanding of the mechanisms through which host epidemiological factors interact with genetic susceptibility to determine breast density may provide insight into the biology of breast cancer and serve to identify women at high risk for whom prevention interventions can be targeted.

Sixth AACR International Conference on Frontiers in Cancer Prevention Research-- Dec 5-8, 2007; Philadelphia, PA