Regulation and Mechanism of Action of the c-Myc Proto-Oncogene in Human Breast Cancer.

Many breast cancers have elevated levels of the c-Myc oncoprotein. c-Myc associates with transcriptional regulator YY1 and inhibits its ability to modulate transcription. Regulating YY1s activity may be an important facet of c-Myc function. Using co-immunoprecipitations we show that the amount of YY1 associated with c-Myc is dependent upon c-Myc levels, consistent with the notion that c-Myc modulates YY1 activity. The region of YY1 required for association has been mapped and association-defective mutants are under study. Another study is underway to determine how normal and mutant YY1 transgenes affect cell growth and development in vivo. We have identified the zinc finger protein Blimp-1 as a repressor of c-myc transcription. Ectopic expression of Blimp-1 can decrease c-Myc levels and cause preB cells to undergo apoptosis. As a repressor of c-myc expression, Blimp-1 might function as a tumor suppressor. Blimp-1 maps to human chromosome 6q22. 1-3--a region sometimes deleted in primary breast cancer, ovarian cancer and non-Hodgkins lymphoma. We will pursue the exciting possibility that Blimp-1 may be inactivated by deletion and mutation in some breast and other cancers.