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Decreased TGFbeta 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 > or = 1.5 with a low false discovery rate (<10%). Network and canonical pathway analysis indicated decreased TGFbeta 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. TGFbeta ligands are currently the only growth factors known to prevent mammary epithelial cell proliferation. TGFbeta 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.

SUBMITTER: Yang WT

PROVIDER: S-EPMC5921048 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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

Yang Wei Tse WT Lewis Michael T MT Hess Kenneth K Wong Helen H Tsimelzon Anna A Karadag Nese N Cairo Michelina M Wei Caimaio C Meric-Bernstam Funda F Brown Powel P Arun Banu B Hortobagyi Gabriel N GN Sahin Aysegul A Chang Jenny C JC

Breast cancer research and treatment 20090225 2

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. Differential ...[more]

PMID: 19241157

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Project description:ImportanceFamily history of breast cancer (FHBC) and mammographic breast density are independent risk factors for breast cancer, but the association of FHBC and mammographic breast density in premenopausal women is not well understood.ObjectivesTo investigate the association of FHBC and mammographic breast density in premenopausal women using both quantitative and qualitative measurements.Design, setting, and participantsThis single-center cohort study examined 2 retrospective cohorts: a discovery set of 375 premenopausal women and a validation set of 14 040 premenopausal women. Data from women in the discovery set was collected between December 2015 and October 2016, whereas data from women in the validation set was collected between June 2010 and December 2015. Data analysis was performed between June 2018 and June 2020.ExposuresFamily history of breast cancer (FHBC).Main outcomes and measuresThe primary outcomes were mammographic breast density measured quantitatively as volumetric percent density using Volpara (discovery set) and qualitatively using BI-RADS (Breast Imaging Reporting and Data System) breast density (validation set). Multivariable regressions were performed using a log-transformed normal distribution for the discovery set and a logistic distribution for the validation set.ResultsOf 14 415 premenopausal women included in the study, the discovery set and validation set had similar characteristics (discovery set with FHBC: mean [SD] age, 47.1 [5.6] years; 15 [17.2%] were Black or African American women and 64 [73.6%] were non-Hispanic White women; discovery set with no FHBC: mean [SD] age, 47.7 [4.5] years; 87 [31.6%] were Black or African American women and 178 [64.7%] were non-Hispanic White women; validation set with FHBC: mean [SD] age, 46.8 [7.3] years; 720 [33.4%] were Black or African American women and 1378 [64.0%] were non-Hispanic White women]; validation set with no FHBC: mean [SD] age, 47.5 [6.1] years; 4572 [38.5%] were Black or African American women and 6632 [55.8%] were non-Hispanic White women]). In the discovery set, participants who had FHBC were more likely to have a higher mean volumetric percent density compared with participants with no FHBC (11.1% vs 9.0%). In the multivariable-adjusted model, volumetric percent density was 25% higher (odds ratio [OR], 1.25 ;95% CI, 1.12-1.41) in women with FHBC compared with women without FHBC; and 24% higher (OR, 1.24; 95% CI, 1.10-1.40) in women who had 1 affected relative, but not significantly higher in women who had at least 2 affected relatives (OR, 1.40; 95% CI, 0.95-2.07) compared with women with no relatives affected. In the validation set, women with a positive FHBC were more likely to have dense breasts (BI-RADS 3-4) compared with women with no FHBC (BI-RADS 3: 41.1% vs 38.8%; BI-RADS 4: 10.5% vs 7.7%). In the multivariable-adjusted model, the odds of having dense breasts (BI-RADS 3-4) were 30% higher (OR, 1.30; 95% CI, 1.17-1.45) in women with FHBC compared with women without FHBC; and 29% higher (OR, 1.29; 95% CI, 1.14-1.45) in women who had 1 affected relative, but not significantly higher in women who had at least 2 affected relatives (OR, 1.38; 95% CI, 0.85-2.23) compared with women with no relatives affected.Conclusions and relevanceIn this cohort study, having an FHBC was positively associated with mammographic breast density in premenopausal women. Our findings highlight the heritable component of mammographic breast density and underscore the need to begin annual screening early in premenopausal women with a family history of breast cancer.

Project description:Mammographic breast density (MBD) is a risk factor for breast cancer, but its molecular basis is poorly understood. Growth factors stimulate cellular and epithelial proliferation and could influence MBD via these mechanisms. Studies investigating the associations of circulating growth factors with MBD have, however, yielded conflicting results especially in postmenopausal women. We, therefore, investigated the associations of plasma growth factor gene expression [insulin-like growth factor (IGF)-1, IGF-binding protein 3, FGF-1, FGF-12, TGFβ1 and bone morphogenetic protein (BMP)-2] with MBD in postmenopausal women. We used NanoString nCounter platform to quantify plasma growth factor gene expression and Volpara to evaluate volumetric MBD measures. We investigated the associations of growth factor gene expression with MBD using both multiple linear regression (fold change) and multinomial logistic regression models, adjusted for potential confounders. The mean age of the 368 women enrolled was 58 years (range, 50-64). In analyses using linear regression models, one unit increase in IGF-1 gene expression was associated with a 35% higher volumetric percent density (VPD, 1.35; 95% confidence interval (CI), 1.13-1.60; P = 0.001). There were suggestions that TGFβ1 gene expression was positively associated with VPD while BMP-2 gene expression was inversely associated with VPD, but these were not statistically significant. In analyses using multinomial logistic regression, TGFβ1 gene expression was 33% higher (OR = 1.33; 95% CI, 1.13-1.56; P = 0.0008) in women with extremely dense breasts than those with almost entirely fatty breasts. There were no associations between growth factor gene expression and dense volume or nondense volume. Our study provides insights into the associations of growth factors with MBD in postmenopausal women and requires confirmation in other study populations.Prevention relevanceMammographic breast density is a strong risk factor for breast cancer. Understanding its underlying biological mechanisms could have utility in breast cancer prevention.

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

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

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