Homeobox Genes in Normal, Preneoplastic, and Neoplastic Mammary Glands

摘要

The overall aim of this project is to improve our understanding of genetic factors regulating the development, differentiation, function, and neoplastic progression of the breast. The homeotic (hox; homeobox) genes are candidates for 'master regulators' of cell fate and tissue interactions. Early in the project we showed that this large family is widely expressed in the mouse and human mammary gland and their tumors, as well as precancerous lesions. Expression was hormonally and developmentally regulated. Hoxa-l was expressed in tumors, but not in normal or preneoplastic tissues. The large numbers of expressed genes and their complex patterns precluded investigation of all, giving rise to a revised and more focused Statement of Work (SOW) following the second annual report. This led to investigation of an engineered mutation in Hoxd-10, which produced a differentiation failure and lactational deficit. We discovered and cloned several members of the Iroquois family of homeotic genes, that we found to be expressed in the normal and neoplastic human breast. Because of the extreme complexity of the expression pattern of hox genes, we turned to the hedgehog (Hh) signaling pathway, not previously shown to be active in the mammary gland, and which has the potential to regulate homeotic genes as well as many other mammary-active pathways. Using engineered mutations in both a Hh receptor and a downstream transcription factor, we demonstrated striking phenotypes characterized by disruption of normal morphogenesis and histogenesis. The discovery of Hh activity in the mammary gland has far reaching implication for both development and cancer.