Breast Stromal Genes Act as Early Markers of Malignancy
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: At present, early detection of breast cancer depends on the radiological and pathological properties (density, architectural distortion, calcifications) of the tumor tissue. These are often non-specific and relatively late changes, and they depend on a tumor of fairly large size (&gt;0.5 cm for mammography) and a late stage of progression. The connective tissue and supporting cells in the breast, called stroma, represent an alternative opportunity to detect the early stages breast cancer. This is because the breast epithelial cells interact with the stroma, and stromal change may occur in parallel or even precede epithelial transformation. The stromal cells do not actually become cancerous themselves, since they remain genetically normal. However, we have reasons to believe that they become influenced by nearby cancer cells to alter their gene expression, such that abundance and presence of certain stromal cellular and secreted proteins could change. Thus, our hypothesis is that examination of stromal gene expression changes resulting from epithelial cell signaling should identify a set of markers that may be used for future molecular diagnosis. This might more accurately reveal tissue that is transitioning into invasive breast cancer.
 
 
 
 
 
 
 
 Our project is a collaboration of expertise and perspectives on breast cancer. Dr. Tlsty is experienced in the basic science signaling processes between epithelial cells and stromal fibroblasts. Dr. Jeffrey is a clinician with research background in breast cancer imaging, treatment, and genetic analysis. Some underlying paradigms for our interest in the stroma include, (i) fibroblasts appear to "instruct" epithelial cells during development, (ii) the stroma and fibroblasts appear to undergo senescence with human aging and this creates a "permissive" state for tumor development, (iii) tumor cells may "signal" stromal fibroblasts in a, so-called, paracrine manner. We hope to address these issues by employing two fundamental approaches. First, we will co-culture fibroblasts and mammary epithelial cells. As part of this approach we will use both "normal" fibroblast and "carcinoma-associated fibroblasts" (CAF). This will allow us to establish a model system to study underlying genetic changes and signaling events associated with fibroblast-epithelial-cancer cell interactions. Secondly, we will employ the method of cDNA microarrays (i.e., "gene chips") to comprehensively analyze the gene "expression profile" that underlie differences in the fibroblast-epithelial-cancer cell interactions associated with breast cancer progression. 
 
 
 
 
 
 
 
 Our aim of this research is to identify specific genetic changes in breast stromal fibroblasts that are associated with specific stages of breast cancer, such as DCIS, various hyperplasia, and different invasive phenotypes. This will lead to molecular "signatures" in the stroma that could be used to both detect breast cancer at an earlier stage and predict disease progression risk. A potential clinical advantage is that the stroma would be expected to be more accessible to specific detection reagents (e.g., antibodies), because it is better exposed to the blood supply and not encased in a basement membrane, which is often the case with pre-invasive tumors.