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

Publication date: 7 March 2017
Source:Cell Reports, Volume 18, Issue 10
Author(s): 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
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.

Graphical abstract

Teaser

Dreijerink et al. describe the oncogenic actions of the tumor suppressor menin in breast cancer cells. In mammary progenitor cells, menin regulates anti-proliferative genes. Menin is present at FOXA1 and GATA3-bound enhancers that associate with promoters through chromatin looping. Insight into menin's context-dependent function suggests therapeutic strategies.


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