Breast Cancer Risk Associated with High Mammographic Density
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: While increased breast density is one of the strongest predictors of breast cancer risk, we know little about its biological basis or how it is associated with increased cancer risk. We do not know if increased breast density is causal or reflective of the mechanisms that lead to increased breast cancer risk. There are influences by genetic, physiologic and environmental factors that generate the tissue phenotypes characteristic of high breast density (excess collagen, tissue remodeling, etc.). These phenotypic characteristics have been observed in conditions where response to tissue remodeling or damage is occurring, such as in mammary gland development (branching morphogenesis), wound healing or the desmoplastic reaction (i.e., the pervasive growth of dense fibrous tissue around the tumor). In these processes, "activated stroma" results in increased levels of collagen and tenascin, stromal remodeling and altered cell cycles for cellular components located within.
 
 
 
 
 
 
 
 We hypothesize that increased breast density may be the end result of biologic processes that result in altered cell-cell and/or cell-extracelluar matrix (ECM) interactions and that these are causal for increased breast cancer risk. Prior work from our laboratory has shown that such altered stroma can dramatically influence tumorigenesis in human models. Proper stromal-epithelial interactions within the ECM can actually suppress the expression of pre-neoplastic phenotypes in epithelial cells and conversely, altered stromal-epithelial interactions can promote the probability that pre-neoplastic lesions progress to malignancy.
 
 
 
 
 
 
 
 If fibroblasts were activated in tissue with high breast density, we would predict that fibroblasts from these tissues would (1) manifest many of the same phenotypes observed in activated stroma (increased collagen, etc.) and (2) possess similar functional properties in facilitating tumor progression of pre-malignant lesions. We will test these predictions within the studies of the proposed application. We will use recombinant grafts of different pairs of fibroblasts and epithelial cells implanted in the mammary fat pad of murine hosts to evaluate cell to cell interactions. Standard tumorigenenic parameters (growth, latency metastasis), cellular characteristics (proliferation and apoptosis) as well as tissue morphology (collagen content, MMP expression, etc.) will be assessed using methodology ongoing in our lab.
 
 
 
 
 
 
 
 Our long-term goal is to identify clinically relevant biomarkers for the early genetic and epigenetic events in carcinogenesis that reflect stromal-epithelial interactions. Our purpose in this study is to determine if fibroblasts from tissue which exhibit high or low mammographic density modulate tissue appearance, tumorigenicity or metastasis. The translational applications of these studies are significant: first, predictive tests could be designed using a molecular imaging ligand attached to an antibody against one or more of the stromal marker gene products for a novel imaging test that may facilitate the detection of tissue at risk for breast cancer, hopefully earlier, less painfully, and more specifically than current mammographic techniques that rely on changes in tissue architecture and density. Second, markers may be identified, tested and then developed into a tissue diagnostic for testing on core needle biopsies that are currently benign but have a high likelihood of developing cancer. Third, a chemical signal may be identified that (in the future) could be assayed in the patient's serum or nipple aspiration fluid leading to the development a simple test for the very early detection of breast cancer risk. Fourth, targets may be identified for the development of novel chemoprevention strategies. Fifth, a mouse model would provide a biologically relevant system to study chemoprevention and/or modulation of human breast density. Although these types of studies are beyond the scope of this grant application, the development a model that would be clinically useful is not. Sixth, novel imaging methodologies may provide improved assessments of biological factors that contribute to breast cancer risk, whether through compositional or metabolic measurements.