) The primary goal of this project is to develop an in vitro system for the transformation of normal human mammary epithelial cells (HMECs) into tumor cells with a defined set of genes. The development of such a system would mark the first time that this has been achieved and greatly enhance our understanding of the genetic requirements for transformation of HMECs in several respects. First, the in vitro transformation of HMECs would allow us to define the minimal requirements for the transformation of these cells and define which cellular signaling pathways must be disrupted for tumorigenic conversion. Second, it would enable us link each genetic mutation with a distinct role in the transformation process. Following the creation of this purely genetic system for the transformation of HMECs, we will refine the model to more accurately reflect the development of human breast cancer in two ways. First, we will replace the initial cohort of transforming genes with genes known to be involved in human breast cancer. This will allow us to classify the genes which have been found to be mutated in breast cancer over the past two decades into groups based on their causal role in the transformation process. Second, we will determine the requirements for tumor formation in the mammary stromal environment by injecting the transformed HMECs into the mouse mammary fat pad and assessing their tumorigenic potential. Lastly, we will investigate the genetic requirements for two of the later stages in breast cancer progression, invasion and metastasis. These requirements will be addressed using both a candidate gene approach and a retroviral cDNA expression screen in order to isolate invasion and metastasis-promoting genes.
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