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

Abstract

High mammographic density is associated with a increased risk of breast cancer. We hypothesized that specific pathways exist that are associated with increased mammographic density, and may therefore be used to identify potential targets for chemoprevention. Histologically confirmed normal breast tissue was collected from women undergoing breast surgery who had available demographic data and mammograms for review. Women with low versus high mammographic breast density were compared. Differentially expressed genes using Affymetrix HG U133Plus2 chips were identified in dense versus non-dense tissue. Immunohistochemical analysis (IHC) of estrogen receptor, progesterone receptor, Ki67, and COX2 expression was performed. About 66 women were identified, 28 (42%) had high, and 38 (58%) had low mammographic density. About 73 genes had differential expression between normal breast tissue with high and low mammographic density (P < 0.001, fold change ≥1.5with a low false discovery rate (<10%). Network and canonical pathway analysis indicated decreased TGFβ signaling (TGFBR2, SOS, SMAD3, CD44 and TNFRSF11B) in dense breast tissue relative to non-dense breast. By IHC, only COX2 expression in the stroma was statistically significant on multivariate analysis. TGFβ ligands are currently the only growth factors known to prevent mammary epithelial cell proliferation. TGFβ signaling has been reported to be inhibited by COX-2, and these molecules are highly differentially expressed in individuals at high risk of developing breast cancer. These results strongly suggest that COX2 inhibition should be investigated for breast cancer prevention despite possible increase in cardiovascular risk.

Breast Density and Breast Cancer Risk: Understanding of Biology and Risk

“…Five studies assessed the association between mammographic density and estrogen receptors (ERα and/or ERβ) and/or progesterone receptor (PR) expression [24,25,[41][42][43]. With the exception of the study by Lundström et al [41], results were null, suggesting that mammographic density is not associated with ER or PR expression in non-cancerous breast tissue.…”

Is Mammographic Density a Biomarker to Study the Molecular Causes of Breast Cancer?

“…In this latter population, a positive association of ER and PgR expression in breast tissue with mammographic density was also observed ). However, none of the other two studies that assessed PgR found any significant association among pre-and/or postmenopausal women (Harvey et al, 2008;Yang et al, 2010).…”

“…So far, two studies assessed the association between the two subtypes of ER, ER and ER , separately and mammographic density (Lundstrom et al, 2006;Verheus et al, 2009), while two others assessed the association between ER, with no mention of the subtype, and mammographic density (Harvey et al, 2008;Yang et al, 2010). Among these, three groups also assessed the association between the progesterone receptor (PgR) and mammographic density (Harvey et al, 2008;Verheus et al, 2009;Yang et al, 2010). …”

“…By inducing prostaglandin E2 synthesis, COX-2 can also promote increased aromatase activity and mRNA production in the mammary gland and thereby augment estrogen production (Subbaramaiah et al, 2008;Zhao et al, 1996). Nevertheless, COX-2 has been shown to inhibit TGF-which is known to reduce mammary epithelial cell proliferation (Studer & Chu, 2005;Yang et al, 2010). In support of this, COX-2 has been found to be up-regulated in 41% and 80% of invasive breast tumors and ductal carcinoma in situ respectively, which is significantly different from the negligible expression in nonneoplastic epithelium (p < 0.0001) (Soslow et al, 2000).…”

“…The hypothesis that specific genetic pathways could influence mammographic density was tested by two research groups (Haakensen et al, 2010;Yang et al, 2010). The first study, described above , used RNA isolated from frozen biopsy specimens from normal breast tissue containing at least 60% epithelial content and obtained at a distance of more than 5 cm from the primary tumor.…”