Maternal or paternal high fat (HF) diet can modify the epigenome in germ
cells and fetal somatic cells leading to an increased susceptibility
among female offspring of multiple generations to develop breast cancer.
We determined if combined treatment with broad spectrum DNA
methyltransferase (DNMT) inhibitor hydralazine and histone deacetylase
(HDAC) inhibitor valproic acid (VPA) will reverse this increased risk.
C57BL/6 mouse dams were fed either a corn oil-based HF or control diet
during pregnancy. Starting at age 7 weeks, female offspring were
administered 3 doses of 7,12-dimethylbenz[a]anthracene (DMBA) to
initiate mammary cancer. After last dose, offspring started receiving
VPA/hydralazine administered via drinking water: no adverse health
effects were detected. VPA/hydralazine reduced mammary tumor
multiplicity and lengthened tumor latency in HF offspring when compared
with non-treated HF offspring. The drug combination inhibited DNMT3a
protein levels and increased expression of the tumor suppressor gene Cdkn2a/p16 in mammary tumors of HF offspring. In control mice not exposed to HF diet in utero, VPA/hydralazine increased mammary tumor incidence and burden, and elevated expression of
the unfolded protein response and autophagy genes, including HIF-1α,
NFkB, PERK, and SQSTM1/p62. Expression of these genes was already
upregulated in HF offspring prior to VPA/hydralazine treatment. These
findings suggest that breast cancer prevention strategies with HDAC/DNMT
inhibitors need to be individually tailored.