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

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Breast Cancer Research

, 19:77

First Online: 03 July 2017Received: 16 December 2016Accepted: 07 June 2017DOI: 10.1186-s13058-017-0866-x

Cite this article as: Nguyen, N.M., de Oliveira Andrade, F., Jin, L. et al. Breast Cancer Res 2017 19: 77. doi:10.1186-s13058-017-0866-x


BackgroundMaternal 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.

MethodsPregnant 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.

ResultsMammary tumor incidence induced by 7,12-dimethylbenzaanthracene 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.

ConclusionsWe 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.

KeywordsBreast cancer Transgenerational n-6 Polyunsaturated fatty acids Primordial germ cells Maternal diet AbbreviationsAKR1C14Aldo-keto reductase family 1, member C14

AKT2Serine-threonine kinase 2


ANKEF1Ankyrin repeat and EF-hand domain containing 1

ANOVAAnalysis of variance

cDNAComplementary DNA

COCorn oil



DEGDifferentially expressed gene

DLL3Delta like canonical Notch ligand 3


DPF3Double PHD fingers 3



EGR3Early growth response 3

EREstrogen receptor

FXR-RXRFarnesoid X receptor-retinoid X receptor

GAPDHGlyceraldehyde 3-phosphate dehydrogenase

GDGestational day

GPCPD1Glycerophosphocholine phosphodiesterase 1

GPCRG protein-coupled receptor

GRHL3Grainyhead like transcription factor 3

GWASGenome-wide association study

HES1Hairy and enhancer of split-1

HFHigh fat

ID4DNA-binding protein inhibitor ID-4

IGF-1Insulin-like growth factor 1

IGF2Insulin-like growth factor 2

IGFBP6Insulin-like growth factor binding protein 6

IPAIngenuity Pathway Analysis

IRF3Interferon regulatory factor 3

IRF7Interferon regulatory factor 7

JAG1Jagged 1

JAM3Junctional adhesion molecule 3

KDDNKnowledge-fused differential dependency network

MAGIXMAGI family member, X-linked

MPAMedroxyprogesterone acetate

MSGN1Mesogenin 1

MT-TS2Mitochondrially encoded transfer RNA serine 2 AGU-C

OAS32′-5′-Oligoadenylate synthetase 3


P21Cyclin-dependent kinase inhibitor 1

PCDHGA8Protocadherin gamma subfamily A, 8

PGCPrimordial germ cell

PNDPostnatal day

PTENPhosphatase and tensin homolog

PUFAPolyunsaturated fatty acid

qPCRQuantitative polymerase chain reaction

qRT-PCRQuantitative real-time polymerase chain reaction

RNA-seqRNA sequencing

SBOSoybean oil

SEMA5BSemaphorin 5B

SFASaturated fatty acid

SLC26A10Solute carrier family 26 member 10

SLC26A3Solute carrier family 26 member 3

SLC5A3Solute carrier family 5 member 3

SLC6A2Solute carrier family 6 member 2

SLFN1Schlafen 1

SNORA41Small nucleolar RNA, H-ACA box 41

SNPSingle-nucleotide polymorphism

STAT5Signal transducer and activator of transcription 5

TBX2T-box 2


TEBTerminal end bud

VDR-RXRVitamin D receptor-retinoid X receptor

ZBP1Z-DNA binding protein 1

ZFP683Zinc finger protein 683

Electronic supplementary materialThe online version of this article doi:10.1186-s13058-017-0866-x contains supplementary material, which is available to authorized users.

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Autor: Nguyen M. Nguyen - Fabia de Oliveira Andrade - Lu Jin - Xiyuan Zhang - Madisa Macon - M. Idalia Cruz - Carlos Benitez - B


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