Targeted DNA Methylation Screen in the Mouse Mammary Genome Reveals a Parity-Induced Hypermethylation of Igf1r That Persists Long after Parturition.
The most effective natural prevention against breast cancer is an early first full-term pregnancy. Understanding how the protective effect is elicited will inform the development of new prevention strategies. To better understand the role of epigenetics in long-term protection, we investigated parity-induced DNA methylation in the mammary gland. FVB mice were bred or remained nulliparous and mammary glands harvested immediately after involution (early) or 6.5 months following involution (late), allowing identification of both transient and persistent changes. Targeted DNA methylation (109 Mb of Ensemble regulatory features) analysis was performed using the SureSelectXT Mouse Methyl-seq assay and massively parallel sequencing. Two hundred sixty-nine genes were hypermethylated and 128 hypomethylated persistently at both the early and late time points. Pathway analysis of the persistently differentially methylated genes revealed Igf1r to be central to one of the top identified signaling networks, and Igf1r itself was one of the most significantly hypermethylated genes. Hypermethylation of Igf1r in the parous mammary gland was associated with a reduction of Igf1r mRNA expression. These data suggest that the IGF pathway is regulated at multiple levels during pregnancy and that its modification might be critical in the protective role of pregnancy. This supports the approach of lowering IGF action for prevention of breast cancer, a concept that is currently being tested clinically.
Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Tiffany A
TA
Katz
Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Serena G
SG
Liao
Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Vincent J
VJ
Palmieri
Department of Biology, University of Texas-Rio Grande Valley, Edinburg, Texas.
Robert K
RK
Dearth
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
Thushangi N
TN
Pathiraja
Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Zhiguang
Z
Huo
Department of Obstetrics. Gynecology, and Reproductive Sciences, University of Pittsburgh, Pennsylvania.
Patricia
P
Shaw
Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Sarah
S
Small
Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Nancy E
NE
Davidson
Department of Obstetrics. Gynecology, and Reproductive Sciences, University of Pittsburgh, Pennsylvania.
David G
DG
Peters
Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.
George C
GC
Tseng
Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. leeav@upmc.edu oesterreichs@upmc.edu.
Steffi
S
Oesterreich
Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. leeav@upmc.edu oesterreichs@upmc.edu.
Adrian V
AV
Lee
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D016678:Genome; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D010298:Parity / Q000235:genetics*; D036801:Parturition; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D017526:Receptor, IGF Type 1 / Q000235:genetics*
D017526:Receptor, IGF Type 1