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

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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.

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Acknowledgments

This study was funded by P50CA116199 grant from the National Cancer Institute (GNH, with a career development award to WTY). This study was supported in part by the Breast Cancer Research Foundation (JCC), the Emma Jacobs Clinical Breast Cancer Fund (JCC), the NCI Breast Cancer SPORE P50 CA50183 (JCC, MTL),1 R01 CA112305-01 from the National Cancer Institute (JCC), P30 CA125123 from the National Institute of Health (JCC).

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Authors and Affiliations

  1. University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

    Wei Tse Yang, Kenneth Hess, Nese Karadag, Caimaio Wei, Funda Meric-Bernstam, Banu Arun, Gabriel N. Hortobagyi & Aysegul Sahin

  2. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Michael T. Lewis, Helen Wong, Anna Tsimelzon, Michelina Cairo, Powel Brown & Jenny C. Chang

  3. Breast Center at Baylor College of Medicine, 1 Baylor Plaza BCM 600, Houston, TX, 77030, USA

    Jenny C. Chang

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  1. Wei Tse Yang
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Correspondence to Wei Tse Yang.

Additional information

Wei Tse Yang and Michael T. Lewis are the co-first authors.

Aysegul Sahin and Jenny C. Chang are the co-senior authors.

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Yang, W.T., Lewis, M.T., Hess, K. et al. Decreased TGFβ signaling and increased COX2 expression in high risk women with increased mammographic breast density. Breast Cancer Res Treat 119, 305–314 (2010). https://doi.org/10.1007/s10549-009-0350-0

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  • DOI: https://doi.org/10.1007/s10549-009-0350-0

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