Abstract 1603: Valproic acid and hydralazine reverse increased mammary cancer risk and upregulate Cdkn2a/p16 in mice exposed to a high fat dietin utero

Abstract

Maternal or paternal high fat (HF) diet that modifies the epigenome in germ cells and fetal somatic cells can program increased susceptibility to breast cancer among offspring. Resulting epigenetic changes include transgenerational upregulation of DNA methyltransferases (DNMTs). We studied here if this increased breast cancer risk can be reversed by treating HF offspring with a well-tolerated drug that inhibits DNA methyl transferase (DNMT; hydralazine), combined with a histone deacetylase (HDAC) inhibitor valproic acid (VPA). Adult C57BL/6NTac mouse offspring of dams fed either corn oil -based HF or control diet during pregnancy were treated with 5 g/kg/day VPA and 5 mg/kg/day hydralazine in drinking water, starting after mice received 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary cancer. Treatment with VPA/hydralazine prevented the increase in mammary cancer risk associated with in utero HF diet exposure: it reduced mammary tumor multiplicity and lengthened tumor latency, compared with non-treated HF offspring. These drugs downregulated DNMT3a protein levels, and reversed down-regulation of Cdkn2a/p16 mRNA in the mammary tumors of HF offspring. p16 is a tumor suppressor that is often epigenetically silenced in human breast cancers. However, in control offspring not exposed to HF diet in utero, VPA/hydralazine increased mammary tumor incidence and burden. Further, this treatment upregulated genes involved in the unfolded protein response pathway in in utero control diet exposed animals that were already upregulated in non-VPA/hydralazine treated mammary tumors from in utero HF diet exposed animals, including HIF-1α, NFkB, PERK and SQSTM1 p62. Thus, VPA and hydralazine had opposing effects on breast cancer risk in HF and control offspring, suggesting the importance of individually tailoring breast cancer prevention strategies. Citation Format: Leena A. Hilakivi-Clarke, Fabia de Oliveira Andrade, Nguyen Nguyen, Kerrie Bouker. Valproic acid and hydralazine reverse increased mammary cancer risk and upregulate Cdkn2a/p16 in mice exposed to a high fat diet in utero [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1603.