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Background  Maternal and paternal high-fat (HF) diet intake before and/or during pregnancy increases mammary cancer risk in several preclinical models. We studied if maternal consumption of a HF diet that began at a time when the fetal primordial germ cells travel to the genital ridge and start differentiating into germ cells would result in a transgenerational inheritance of increased mammary cancer risk.    Methods  Pregnant C57BL/6NTac mouse dams were fed either a control AIN93G or isocaloric HF diet composed of corn oil high in n-6 polyunsaturated fatty acids between gestational days 10 and 20. Offspring in subsequent F1–F3 generations were fed only the control diet.    Results  Mammary tumor incidence induced by 7,12-dimethylbenz[a]anthracene was significantly higher in F1 ( p  < 0.016) and F3 generation offspring of HF diet-fed dams ( p  < 0.040) than in the control offspring. Further, tumor latency was significantly shorter ( p  < 0.028) and burden higher ( p  < 0.027) in F1 generation HF offspring, and similar trends were seen in F3 generation HF offspring. RNA sequencing was done on normal mammary glands to identify signaling differences that may predispose to increased breast cancer risk by maternal HF intake. Analysis revealed 1587 and 4423 differentially expressed genes between HF and control offspring in F1 and F3 generations, respectively, of which 48 genes were similarly altered in both generations. Quantitative real-time polymerase chain reaction analysis validated 13 chosen up- and downregulated genes in F3 HF offspring, but only downregulated genes in F1 HF offspring. Ingenuity Pathway Analysis identified upregulation of Notch signaling as a key alteration in HF offspring. Further, knowledge-fused differential dependency network analysis identified ten node genes that in the HF offspring were uniquely connected to genes linked to increased cancer risk ( ANKEF1 ,  IGFBP6 ,  SEMA5B ), increased resistance to cancer treatments ( SLC26A3 ), poor prognosis ( ID4 ,  JAM3 ,  TBX2 ), and impaired anticancer immunity ( EGR3 ,  ZBP1 ).    Conclusions  We conclude that maternal HF diet intake during pregnancy induces a transgenerational increase in offspring mammary cancer risk in mice. The mechanisms of inheritance in the F3 generation may be different from the F1 generation because significantly more changes were seen in the transcriptome.    Electronic supplementary material  The online version of this article (doi:10.1186/s13058-017-0866-x) contains supplementary material, which is available to authorized users.

Maternal intake of high n-6 polyunsaturated fatty acid diet during pregnancy causes transgenerational increase in mammary cancer risk in mice