Mammographic breast density is a strong predictor of breast cancer risk. Women with radiodense areas? covering greater than 50% of the tissue area have a 3 to 5 fold increase in risk for breast cancer compared? with women with little or no radiodense area. It is estimated that almost 1/3 of breast cancer incidence is? due to biological variables (both genetic and environmental) that modulate breast density. Given this? strong correlation between breast density and risk for breast cancer, it is surprising that so little is known? about the character or origin of dense breast tissue.? We hypothesize that the molecular interactions between stroma and epithelium represent some of? the very first changes that occur within breast tissue allowing malignant transformation and may therefore? serve as a predictor of breast cancer in its earliest stages. We propose that features of increased stromal? remodeling noted in the extracellular matrix (ECM) and molecular markers in mammographically dense? breasts are indicative of an 'activated' stroma. Activated stroma (AS) is similar to stroma formed during? normal, non-pathological processes such as morphogenesis and wound healing, and can also be found in? pathological states such as desmoplasia. While normal stromal-epithelial interactions actively suppress? preneoplastic phenotypes, activated stroma can become an active participant in cancer progression. We? hypothesize that the mechanistic links between high breast density and increased breast cancer? risk lie in the signal transduction pathways that lead to increased breast density and? concomitantly promote malignant progression in initiated cells in the adjacent epithelium. This? proposal will examine several aspects of the phenotypic, molecular and functional differences of? mammary fibroblasts and epithelial cells isolated from individuals with high or low mammographic density? that have or have not developed breast cancer. Histologic and molecular evaluation of these tissues will? provide novel markers that define increased breast density and increased cancer risk. In Project 2, we will? 1) Determine the cellular and histological composition of human breast tissues with high and low? mammographic density. A three-dimensional reconstruction (3D) of the gland, linked to the BioSig? database, will integrate this morphologic data with molecular data. (2) Using cDNA microarrays, we will? compare expression profiles from tissues with high and low mammographic densities (a) to each other? and (b) to matched tissues from individuals that have developed cancer at a distant site. These markers? can be used in Project 3 to evaluate paraffin-preserved benign breast biopsy tissue by immunostains for? association of risk for breast cancer.
In Specific Aim 3 In vivo and in vitro recombinant experiments will? provide insights into the cell combinations that generate increased breast density and molecular markers? associated with increased breast cancer risk. (3) Finally we will determine the functional phenotype of? fibroblast cells obtained from human breast tissues with high and low mammographic density. We have? found that fibroblasts from tissue with high mammographic density retain differential expression of? biologically relevant pathways such as the IGF-axis. These fibroblasts have been demonstrated to? facilitate tumor progression when placed in a murine recombinant model. The proposed studies will? determine the molecular basis for fibroblast enhancement of tumorigenic phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA107584-02
Application #
7488334
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$220,323
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Gascard, Philippe; Tlsty, Thea D (2016) Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev 30:1002-19
Rees, Elliott; Kendall, Kimberley; Pardiñas, Antonio F et al. (2016) Analysis of Intellectual Disability Copy Number Variants for Association With Schizophrenia. JAMA Psychiatry 73:963-969
Drake, Christopher R; Estévez-Salmerón, Luis; Gascard, Philippe et al. (2015) Towards aspirin-inspired self-immolating molecules which target the cyclooxygenases. Org Biomol Chem 13:11078-86
DeFilippis, Rosa Anna; Fordyce, Colleen; Patten, Kelley et al. (2014) Stress signaling from human mammary epithelial cells contributes to phenotypes of mammographic density. Cancer Res 74:5032-5044
Roy, Somdutta; Gascard, Philippe; Dumont, Nancy et al. (2013) Rare somatic cells from human breast tissue exhibit extensive lineage plasticity. Proc Natl Acad Sci U S A 110:4598-603
Kerlikowske, Karla; Zhu, Weiwei; Hubbard, Rebecca A et al. (2013) Outcomes of screening mammography by frequency, breast density, and postmenopausal hormone therapy. JAMA Intern Med 173:807-16
Braithwaite, Dejana; Mandelblatt, Jeanne S; Kerlikowske, Karla (2013) To screen or not to screen older women for breast cancer: a conundrum. Future Oncol 9:763-6
Dumont, Nancy; Liu, Bob; Defilippis, Rosa Anna et al. (2013) Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia 15:249-62
DeFilippis, Rosa Anna; Chang, Hang; Dumont, Nancy et al. (2012) CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues. Cancer Discov 2:826-39
Fordyce, Colleen A; Patten, Kelley T; Fessenden, Tim B et al. (2012) Cell-extrinsic consequences of epithelial stress: activation of protumorigenic tissue phenotypes. Breast Cancer Res 14:R155

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