title: Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer.
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.
authors.affiliation: 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.
authors.forename: Koen M A
authors.initials: KMA
authors.lastname: Dreijerink
authors.affiliation: 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.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Groner
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Erica S M
authors.initials: ESM
authors.lastname: Vos
authors.affiliation: 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.
authors.forename: Alba
authors.initials: A
authors.lastname: Font-Tello
authors.affiliation: Division of Newborn Medicine, Children's Hospital Boston and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Chi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Reyes
authors.affiliation: 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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cook
authors.affiliation: 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.
authors.forename: Elgene
authors.initials: E
authors.lastname: Lim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA.
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: de Laat
authors.affiliation: 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.
authors.forename: Prakash K
authors.initials: PK
authors.lastname: Rao
authors.affiliation: 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.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Long
authors.affiliation: 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.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D050990:GATA3 Transcription Factor; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D004958:Estradiol; D008239:Lysine
keywords: MEN1; breast cancer; enhancer; epigenetics; histone H3K4 trimethylation; menin; oncogene; transcription; tumor suppressor