Two areas in mammary gland biology are of interest to this laboratory. The mechanisms employed to activate transcription of milk protein genes during pregnancy, and the genetic switches that turn the mammary anlage into a functional organ. The whey acidic protein (WAP) gene serves as a paradigm to understand gene regulation in the mammary gland. Genetic switches and mechanisms have been identified which control the regulation of the WAP gene. Activation of WAP genes during pregnancy is mediated through transcription factors from the Ets family which bind to a specific sequence in the promoter. This illustrated that Ets signalling pathways can function as stage specific transcriptional activators in the mammary gland during pregnancy. Experiments were performed to understand genetic pathways which mediate the growth and differentiation of mammary tissue during puberty and pregnancy. It was determined at the molecular level that the mammary gland goes through several differentiation phases during development. Mammary epithelial cells undergo secretory differentiation in virgins during the estrus cycle, but require pregnancy for the establishment of terminal differentiation. These mechanistic studies provided the explanation for earlier findings by us and others that virgin transgenic mice carrying oncogenes can develop tumors, just like in human. In these cases oncogenes are activated during the estrus cycle in virgins and transform cells prior to pregnancy. Studies on mice with a non-functional CSF-1 gene revealed that CSF-1 is required for functional differentiation of mammary tissue.
