Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival

• Published in: The FASEB journal Vol. 23; no. 4; pp. 1054 - 1063
• Main Authors: Kovacheva, Vesela P, Davison, Jessica M, Mellott, Tiffany J, Rogers, Adrianne E, Yang, Shi, O'Brien, Michael J, Blusztajn, Jan Krzysztof
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01.04.2009
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - metabolism; Adenocarcinoma - chemically induced; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Carcinogens - metabolism; Choline - metabolism; Choline Deficiency - metabolism; Cluster Analysis; Female; Fetus - embryology; Fetus - metabolism; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Immunohistochemistry; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Pregnancy; Prenatal Exposure Delayed Effects - metabolism; Rats; Rats, Sprague-Dawley; Survival Analysis; Time Factors
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.08-122168

Choline is an essential nutrient that serves as a donor of metabolic methyl groups used during gestation to establish the epigenetic DNA methylation patterns that modulate tissue-specific gene expression. Because the mammary gland begins its development prenatally, we hypothesized that choline availability in utero may affect the gland's susceptibility to cancer. During gestational days 11-17, pregnant rats were fed a control, choline-supplemented, or choline-deficient diet (8, 36, and 0 mmol/kg of choline, respectively). On postnatal day 65, the female offspring received 25 mg/kg of a carcinogen 7,12-dimethylbenz[α]anthracene. Approximately 70% of the rats developed mammary adenocarcinomas; prenatal diet did not affect tumor latency, incidence, size, and multiplicity. Tumor growth rate was inversely related to choline content in the prenatal diet, resulting in 50% longer survival until euthanasia, determined by tumor size, of the prenatally choline-supplemented rats compared with the prenatally choline-deficient rats. This was accompanied by distinct expression patterns of ~70 genes in tumors derived from the three dietary groups. Tumors from the prenatally choline-supplemented rats overexpressed genes that confer favorable prognosis in human cancers (Klf6, Klf9, Nid2, Ntn4, Per1, and Txnip) and underexpressed those associated with aggressive disease (Bcar3, Cldn12, Csf1, Jag1, Lgals3, Lypd3, Nme1, Ptges2, Ptgs1, and Smarcb1). DNA methylation within the tumor suppressor gene, stratifin (Sfn, 14-3-3σ), was proportional to the prenatal choline supply and correlated inversely with the expression of its mRNA and protein in tumors, suggesting that an epigenetic mechanism may underlie the altered molecular phenotype and tumor growth. Our results suggest a role for adequate maternal choline nutrition during pregnancy in prevention/alleviation of breast cancer in daughters.--Kovacheva, V. P., Davison, J. M., Mellott, T. J., Rogers, A. E., Yang, S., O'Brien, M. J., Blusztajn, J. K. Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival. (2009)