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Cell Rep. 2017 Mar 7;18(10):2359-2372. doi: 10.1016/j.celrep.2017.02.025.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA.
2
Hubrecht Institute-KNAW and University Medical Center, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
3
Division of Newborn Medicine, Children's Hospital Boston and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA. Electronic address: myles_brown@dfci.harvard.edu.

Abstract

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.

KEYWORDS:

MEN1; breast cancer; enhancer; epigenetics; histone H3K4 trimethylation; menin; oncogene; transcription; tumor suppressor

PMID:
28273452
PMCID:
PMC5609449
DOI:
10.1016/j.celrep.2017.02.025
[Indexed for MEDLINE]
Free PMC Article

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