Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

oleh: Koen M.A. Dreijerink, Anna C. Groner, Erica S.M. Vos, Alba Font-Tello, Lei Gu, David Chi, Jaime Reyes, Jennifer Cook, Elgene Lim, Charles Y. Lin, Wouter de Laat, Prakash K. Rao, Henry W. Long, Myles Brown

Format: Article
Diterbitkan: Elsevier 2017-03-01

Deskripsi

While the multiple endocrine neoplasia type 1 (MEN1) gene functions as a tumor suppressor in a variety of cancer types, we explored its oncogenic role in breast tumorigenesis. The MEN1 gene product menin is involved in H3K4 trimethylation and co-activates transcription. We integrated ChIP-seq and RNA-seq data to identify menin target genes. Our analysis revealed that menin-dependent target gene promoters display looping to distal enhancers that are bound by menin, FOXA1 and GATA3. In this fashion, MEN1 co-regulates a proliferative breast cancer-specific gene expression program in ER+ cells. In primary mammary cells, MEN1 exerts an anti-proliferative function by regulating a distinct expression signature. Our findings clarify the cell-type-specific functions of MEN1 and inform the development of menin-directed treatments for breast cancer.