Regulation and Mechanism of Action of the c-Myc Proto-Oncogene in Human BreastCancer

摘要

Our studies on transcriptional regulation of the c-myc proto-oncogen are dividedinto two subprojects: i) studies on Blimp-1, a transcriptional repressor of c-myc and ii) studies to determine the mechanism by which estrogen induces c-myc transcription in estrogen-dependent breast cancer cells. Blimp-1 was initially identified as a master-regulator of B-lymphocyte differentiation and was thought to be B-cell specific. We recently showed that Blimp-1 is a site specific repressor of c-myc ye transcription. Our studies reported here provide evidence that Blimp-1 plays a role in terminal differentiation of many cell lineages. We show that Blimp-1 mRNA is induced upon terminal differentiation of promyelocytic cells in culture and that Blimp-1 mRNA is present in many adult tissues. We have also demonstrated the ability of Blimp-1 to repress growth of MCF-7 breast cancer cells, which depend upon c-Myc activity for their transformed growth. In the second project, runon transcription has been used to show that estrogen induces transcription initiation but does not alter polymerase processivity on the c-myc gene in MCF-7 cells. We have identified four DNaseI hypersensitivity sites in the c-myc gene which are induced in response to estrogen. They are good candidates to be unusual estrogen response elements.