Decreased TGFβ signaling and increased COX2 expression in high risk women with increased mammographic breast density.

Abstract

Abstract Abstract #1107 Background
 High mammographic density is associated with up to a 6-fold increased risk of breast cancer. Pathways responsible for this increased density are unknown. We hypothesize that specific molecular pathways exist that are associated with increased mammographic density and breast cancer risk, and may therefore be used to identify potential targets for chemoprevention.
 Methods
 Histologically confirmed normal breast tissue was collected from women undergoing breast surgery who had available demographic data and mammograms for review. Breast parenchymal density was classified according to the American College of Radiology's Breast Imaging – Reporting and Data System reporting system. Quantitative classification of mammographic parenchyma was performed using thresholding method and percent density. Women with low (less than 50%) versus high (greater than 50%) breast density were compared. Double-stranded cDNA was synthesized from the normal breast tissue using an oligo-dT primer containing a T7 RNA polymerase promoter, followed by in vitro transcription with biotinylated ribonucleotides. The labeled cRNA was hybridized to Affymetrix HG U133Plus2 chips which comprise ∼28,600 genes to determine gene expression patterns. Immunohistochemical analysis (IHC) of estrogen receptor, progesterone receptor, proliferation (Ki67) and COX2 expression was performed.
 Results
 Sixty-two women were identified, 26 (42%) had high, and 36 (58%) had low mammographic density. Neither age, menopausal nor hormone receptor status influenced the gene expression pattern. Seventy-three genes had differential expression between normal breast tissue with high and low mammographic density (p<0.001, fold change>1.5) and had a low false discovery rate (<10%). Of these 73 differentially expressed genes, network and canonical pathway analysis demonstrate decreased TGFβ signaling (TGFBR2, SOS, SMAD3 and CD44 expression) in dense breast relative to non-dense breast. By IHC, Ki67 (stroma) and COX2 expression were significantly higher in dense breasts (p<0.05) on univariate analysis, and only COX2 expression in the stroma was statistically significant at (p<0.01) on multivariate analysis.
 Conclusion
 TGFβ ligands are currently the only growth factors known to prevent mammary epithelial cell proliferation. TGFβ has been reported to influence COX-2 expression, and these molecules are highly differentially expressed in individuals at high risk of developing breast cancer. These results suggest that COX2 inhibition should be further investigated for breast cancer prevention despite possible increase in cardiovascular risk. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1107.