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

doi:10.1016/j.celrep.2017.02.025

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

61 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2359-2372
Number of pages	14
Journal	Cell Reports
Volume	18
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2017.02.025
Publication status	Published - 07 Mar 2017

Keywords

Breast Neoplasms
Cell Line, Tumor
Cell Proliferation
Enhancer Elements, Genetic
Estradiol
Estrogen Receptor alpha
Female
GATA3 Transcription Factor
Gene Expression Regulation, Neoplastic
Genomics
Hepatocyte Nuclear Factor 3-alpha
Histones
Humans
Lysine
Methylation
Oncogenes
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Proteins
Transcription, Genetic
Journal Article

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10.1016/j.celrep.2017.02.025

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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.",

keywords = "Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Enhancer Elements, Genetic, Estradiol, Estrogen Receptor alpha, Female, GATA3 Transcription Factor, Gene Expression Regulation, Neoplastic, Genomics, Hepatocyte Nuclear Factor 3-alpha, Histones, Humans, Lysine, Methylation, Oncogenes, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Transcription, Genetic, Journal Article",

author = "Dreijerink, {Koen M A} and Groner, {Anna C} and Vos, {Erica S M} and Alba Font-Tello and Lei Gu and David Chi and Jaime Reyes and Jennifer Cook and Elgene Lim and Lin, {Charles Y} and {de Laat}, Wouter and Rao, {Prakash K} and Long, {Henry W} and Myles Brown",

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doi = "10.1016/j.celrep.2017.02.025",

language = "English",

volume = "18",

pages = "2359--2372",

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T1 - Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

AU - Dreijerink, Koen M A

AU - Groner, Anna C

AU - Vos, Erica S M

AU - Font-Tello, Alba

AU - Gu, Lei

AU - Chi, David

AU - Reyes, Jaime

AU - Cook, Jennifer

AU - Lim, Elgene

AU - Lin, Charles Y

AU - de Laat, Wouter

AU - Rao, Prakash K

AU - Long, Henry W

AU - Brown, Myles

PY - 2017/3/7

Y1 - 2017/3/7

N2 - 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.

AB - 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.

KW - Breast Neoplasms

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Enhancer Elements, Genetic

KW - Estradiol

KW - Estrogen Receptor alpha

KW - Female

KW - GATA3 Transcription Factor

KW - Gene Expression Regulation, Neoplastic

KW - Genomics

KW - Hepatocyte Nuclear Factor 3-alpha

KW - Histones

KW - Humans

KW - Lysine

KW - Methylation

KW - Oncogenes

KW - Promoter Regions, Genetic

KW - Protein Binding

KW - Proto-Oncogene Proteins

KW - Transcription, Genetic

KW - Journal Article

U2 - 10.1016/j.celrep.2017.02.025

DO - 10.1016/j.celrep.2017.02.025

M3 - Article

C2 - 28273452

SN - 2211-1247

VL - 18

SP - 2359

EP - 2372

JO - Cell Reports

JF - Cell Reports

IS - 10

ER -

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

Abstract

Keywords

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