Targeted DNA Methylation Screen in the Mouse Mammary Genome Reveals a Parity-Induced Hypermethylation of Igf1r That Persists Long After Parturition

Overview

Journal Cancer Prev Res (Phila)

Specialty Oncology

Date 2015 Aug 21

PMID 26290394

Citations 14

Authors

Tiffany A Katz

Serena G Liao

Vincent J Palmieri

Robert K Dearth

Thushangi N Pathiraja

Zhiguang Huo

Patricia Shaw

Sarah Small

Nancy E Davidson

David G Peters

George C Tseng

Steffi Oesterreich

Adrian V Lee

Affiliations

Soon will be listed here.

Abstract

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.

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References

Zhang Y, Kensler T, Cho C, Posner G, Talalay P . Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci U S A. 1994; 91(8):3147-50. PMC: 43532. DOI: 10.1073/pnas.91.8.3147. View

MacMahon B, Cole P, Lin T, Lowe C, MIRRA A, RAVNIHAR B . Age at first birth and breast cancer risk. Bull World Health Organ. 1970; 43(2):209-21. PMC: 2427645. View

Raafat A, Strizzi L, Lashin K, Ginsburg E, McCurdy D, Salomon D . Effects of age and parity on mammary gland lesions and progenitor cells in the FVB/N-RC mice. PLoS One. 2012; 7(8):e43624. PMC: 3431359. DOI: 10.1371/journal.pone.0043624. View

Jerry D, Makari-Judson G, Crisi G, Dunphy K . Pregnancy offers new insights into mechanisms of breast cancer risk and resistance. Breast Cancer Res. 2013; 15(5):312. PMC: 3979118. DOI: 10.1186/bcr3482. View

Kleinberg D, Feldman M, Ruan W . IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis. J Mammary Gland Biol Neoplasia. 2000; 5(1):7-17. DOI: 10.1023/a:1009507030633. View

Dearth R, Delgado D, Hiney J, Pathiraja T, Oesterreich S, Medina D . Parity-induced decrease in systemic growth hormone alters mammary gland signaling: a potential role in pregnancy protection from breast cancer. Cancer Prev Res (Phila). 2010; 3(3):312-21. PMC: 2833223. DOI: 10.1158/1940-6207.CAPR-09-0074. View

Russo I, Russo J . Pregnancy-induced changes in breast cancer risk. J Mammary Gland Biol Neoplasia. 2011; 16(3):221-33. DOI: 10.1007/s10911-011-9228-y. View

Yang D, Baumgartner R, Slattery M, Wang C, Giuliano A, Murtaugh M . Dietary intake of folate, B-vitamins and methionine and breast cancer risk among Hispanic and non-Hispanic white women. PLoS One. 2013; 8(2):e54495. PMC: 3569453. DOI: 10.1371/journal.pone.0054495. View

Bassett J, Baglietto L, Hodge A, Severi G, Hopper J, English D . Dietary intake of B vitamins and methionine and breast cancer risk. Cancer Causes Control. 2013; 24(8):1555-63. DOI: 10.1007/s10552-013-0232-y. View

10.

Barton M, Santucci-Pereira J, Russo J . Molecular pathways involved in pregnancy-induced prevention against breast cancer. Front Endocrinol (Lausanne). 2014; 5:213. PMC: 4261797. DOI: 10.3389/fendo.2014.00213. View

11.

Bock C, Reither S, Mikeska T, Paulsen M, Walter J, Lengauer T . BiQ Analyzer: visualization and quality control for DNA methylation data from bisulfite sequencing. Bioinformatics. 2005; 21(21):4067-8. DOI: 10.1093/bioinformatics/bti652. View

12.

Lawrence M, Huber W, Pages H, Aboyoun P, Carlson M, Gentleman R . Software for computing and annotating genomic ranges. PLoS Comput Biol. 2013; 9(8):e1003118. PMC: 3738458. DOI: 10.1371/journal.pcbi.1003118. View

13.

Zhang B, Zhou Y, Lin N, Lowdon R, Hong C, Nagarajan R . Functional DNA methylation differences between tissues, cell types, and across individuals discovered using the M&M algorithm. Genome Res. 2013; 23(9):1522-40. PMC: 3759728. DOI: 10.1101/gr.156539.113. View

14.

Schonfeld S, Pfeiffer R, Lacey Jr J, Berrington de Gonzalez A, Doody M, Greenlee R . Hormone-related risk factors and postmenopausal breast cancer among nulliparous versus parous women: An aggregated study. Am J Epidemiol. 2011; 173(5):509-17. PMC: 3105439. DOI: 10.1093/aje/kwq404. View

15.

Ghoshal K, Li X, Datta J, Bai S, Pogribny I, Pogribny M . A folate- and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of F344 rats. J Nutr. 2006; 136(6):1522-7. PMC: 2237890. DOI: 10.1093/jn/136.6.1522. View

16.

Pike M, Pearce C, Wu A . Prevention of cancers of the breast, endometrium and ovary. Oncogene. 2004; 23(38):6379-91. DOI: 10.1038/sj.onc.1207899. View

17.

Sun Z, Shushanov S, LeRoith D, Wood T . Decreased IGF type 1 receptor signaling in mammary epithelium during pregnancy leads to reduced proliferation, alveolar differentiation, and expression of insulin receptor substrate (IRS)-1 and IRS-2. Endocrinology. 2011; 152(8):3233-45. PMC: 3138223. DOI: 10.1210/en.2010-1296. View

18.

Ruan W, Fahlbusch F, Clemmons D, Monaco M, Walden P, Silva A . SOM230 inhibits insulin-like growth factor-I action in mammary gland development by pituitary independent mechanism: mediated through somatostatin subtype receptor 3?. Mol Endocrinol. 2005; 20(2):426-36. DOI: 10.1210/me.2005-0283. View

19.

Rajkumar L, Guzman R, Yang J, Thordarson G, Talamantes F, Nandi S . Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis. Proc Natl Acad Sci U S A. 2001; 98(20):11755-9. PMC: 58802. DOI: 10.1073/pnas.201393798. View

20.

Fisher B, Costantino J, Wickerham D, Redmond C, Kavanah M, Cronin W . Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998; 90(18):1371-88. DOI: 10.1093/jnci/90.18.1371. View