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3D BREAST TISSUE CO-CULTURES FOR SCREENING MAMMARY CARCINOGENS - PHASE I
Description:
Breast cancer is not a disease of individual cells, but principally a failure of cells and tissues to communicate properly. One communication mechanism that is frequently disrupted in breast cancer involves the hormone estrogen. Despite recognition that exposure to compounds with estrogenic activity can promote breast cancer formation and progression, no good mechanistic explanation presently exists for how this actually happens. Previously, the inability to stably culture endocrine reception positive (Era[+])) cells from normal human breast tissue impeded the mechanistic study of the acquisition of proliferative potential by such cells. A three-dimensional (3D) human breast tissue co-culture model will be developed that sustains Era(+) cells along with all cell types of breast tissue. The physiologically relevant co-culture model will be treated with prototypical mammary gland carcinogens to demonstrate increased co-expression of Era and proliferative markers such as Ki67, indicating disordered control of cell division, which may represent an important early pathogenic step in the development of breast cancer. This new experimentally manipulable system will enable quick and efficient determination of both genetic and environmental factors that cause deregulated co-expression of Era and proliferative markers in human breast cells. In our proposed studies, we will make use of this new experimental system to determine whether known carcinogens can cause the emergence of proliferative Era(+) breast cells, and to understand the mechanisms responsible for this preneoplastic change. Knowledge of the mechanisms involved will enable the design of better carcinogen screening methods and prevention measures. Proposed Phase II studies would integrate the 3D breast tissue co-culture into existing high throughput screening and imaging platforms such as EPA’s ToxCast and NIH’s Chemical Genomic Center (NCGC) High Throughput Screening (HTS) system, enabling the differentiation of proliferating agents from carcinogens, classification of carcinogenic agents such as genotoxins from non-genotoxins, and environmental risk assessment in life-cycle stages.