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

• Published in: Cell reports (Cambridge) Vol. 18; no. 10; pp. 2359 - 2372
• Main Authors: Dreijerink, Koen M.A., Groner, Anna C., Vos, Erica S.M., Font-Tello, Alba, Gu, Lei, Chi, David, Reyes, Jaime, Cook, Jennifer, Lim, Elgene, Lin, Charles Y., de Laat, Wouter, Rao, Prakash K., Long, Henry W., Brown, Myles
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.03.2017; Elsevier
• Subjects: breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation; enhancer; Enhancer Elements, Genetic - genetics; epigenetics; Estradiol - pharmacology; Estrogen Receptor alpha - metabolism; Female; GATA3 Transcription Factor - metabolism; Gene Expression Regulation, Neoplastic; Genomics; Hepatocyte Nuclear Factor 3-alpha - metabolism; histone H3K4 trimethylation; Histones - metabolism; Humans; Lysine - metabolism; MEN1; menin; Methylation; oncogene; Oncogenes; Promoter Regions, Genetic; Protein Binding - drug effects; Proto-Oncogene Proteins - genetics; transcription; Transcription, Genetic; tumor suppressor; enhancer; histone H3K4 trimethylation; transcription; menin; breast cancer; tumor suppressor; oncogene; epigenetics; MEN1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.02.025

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. [Display omitted] •The MEN1 gene product, menin, has an oncogenic role in ER+ breast cancer cells•The breast cancer driver gene ESR1 is a major menin target gene in ER+ cells•Menin is present at FOXA1 and GATA3-bound enhancers that are looped to promoters•Enhancer presence of menin marks target gene H3K4me3 and transcription 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.