Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer
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
Affiliations
Koen M.A. Dreijerink
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
Anna C. Groner
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
Erica S.M. Vos
Hubrecht Institute-KNAW and University Medical Center, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
Alba Font-Tello
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
Lei Gu
Division of Newborn Medicine, Children’s Hospital Boston and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
David Chi
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
Jaime Reyes
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
Jennifer Cook
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
Elgene Lim
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
Charles Y. Lin
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
Wouter de Laat
Hubrecht Institute-KNAW and University Medical Center, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
Prakash K. Rao
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
Henry W. Long
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
Myles Brown
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston 02215, MA, USA
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.
