Attempts at understanding the detailed molecular mechanisms of breast cancer pathogenesis have been frustrated in part by the lack of experimental models that adequately recapitulate the biological attributes of normal and neoplastic human breast tissues. This shortcoming has inspired the construction of human mammary gland tissue in immunocompromised mice that appears to function in a fashion that closely resembles that of the normal human mammary gland. With the availability of this model, the precise biological and morphogenetic actions of various genes that are thought to participate in human breast pathogenesis can be examined. The mechanisms that lead to the hyperplasias seen in the human breast epithelium are still poorly understood. Prolactin (Prl) of pituitary origin is normally involved in promoting the development of the mammary gland late in pregnancy. Research to be conducted examines how Prl is able to elicit histopathological alterations in the mammary epithelium that represent early steps of tumor progression. A genetically altered mouse model that has been developed will prove highly useful in elucidating the biochemical changes in mammary epithelial cells (MECs) that are directly induced by the ligand-activated Prl receptor. A third line of research addresses the molecular mechanisms that enable tumorigenic but non-invasive MECs to acquire the traits that enable such cells to invade and metastasize. Three transcription factors (TFs) have been characterized that are capable of activating the epithelial-tomesenchymal transformation (EMT) that appears to be closely linked to the acquired ability of MECs to invade and thereafter to metastasize. Detailed research will be focused here specifically on the Goosecoid TF. On the one hand, expression of this TF can be induced in epithelial cells by TGF, a protein that has frequently been associated with the invasive front of primary tumors. On the other, Goosecoid is capable of programming many of the changes associated with the EMT, including loss of epithelial markers, acquisition of mesenchymal markers, and increased motility. The functional relationships between Goosecoid and two other TFs that function analogously will be explored in an attempt to determine whether a single signaling circuit involving these three TFs is responsible for programming all types of cancer-associated invasiveness, or whether different TFs are associated with distinct invasion-controlling regulatory circuits in human MECs.
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