PMID- 30165877 OWN - NLM STAT- MEDLINE DCOM- 20190522 LR - 20190522 IS - 1465-542X (Electronic) IS - 1465-5411 (Print) IS - 1465-5411 (Linking) VI - 20 IP - 1 DP - 2018 Aug 30 TI - Paternal malnutrition programs breast cancer risk and tumor metabolism in offspring. PG - 99 LID - 10.1186/s13058-018-1034-7 [doi] LID - 99 AB - BACKGROUND: While many studies have shown that maternal factors in pregnancy affect the cancer risk for offspring, few studies have investigated the impact of paternal exposures on their progeny's risk of this disease. Population studies generally show a U-shaped association between birthweight and breast cancer risk, with both high and low birthweight increasing the risk compared with average birthweight. Here, we investigated whether paternal malnutrition would modulate the birthweight and later breast cancer risk of daughters. METHODS: Male mice were fed AIN93G-based diets containing either 17.7% (control) or 8.9% (low-protein (LP)) energy from protein from 3 to 10 weeks of age. Males on either group were mated to females raised on a control diet. Female offspring from control and LP fathers were treated with 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary carcinogenesis. Mature sperm from fathers and mammary tissue and tumors from female offspring were used for epigenetic and other molecular analyses. RESULTS: We found that paternal malnutrition reduces the birthweight of daughters and leads to epigenetic and metabolic reprogramming of their mammary tissue and tumors. Daughters of LP fathers have higher rates of mammary cancer, with tumors arising earlier and growing faster than in controls. The energy sensor, the AMP-activated protein kinase (AMPK) pathway, is suppressed in both mammary glands and tumors of LP daughters, with consequent activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, LP mammary tumors show altered amino-acid metabolism with increased glutamine utilization. These changes are linked to alterations in noncoding RNAs regulating those pathways in mammary glands and tumors. Importantly, we detect alterations in some of the same microRNAs/target genes found in our animal model in breast tumors of women from populations where low birthweight is prevalent. CONCLUSIONS: Our study suggests that ancestral paternal malnutrition plays a role in programming offspring cancer risk and phenotype by likely providing a metabolic advantage to cancer cells. FAU - da Cruz, Raquel Santana AU - da Cruz RS AD - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, The Research Building, Room E410, Washington, DC, 20057, USA. FAU - Carney, Elissa J AU - Carney EJ AD - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, The Research Building, Room E410, Washington, DC, 20057, USA. FAU - Clarke, Johan AU - Clarke J AD - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, The Research Building, Room E410, Washington, DC, 20057, USA. FAU - Cao, Hong AU - Cao H AD - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, The Research Building, Room E410, Washington, DC, 20057, USA. FAU - Cruz, M Idalia AU - Cruz MI AD - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, The Research Building, Room E410, Washington, DC, 20057, USA. FAU - Benitez, Carlos AU - Benitez C AD - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, The Research Building, Room E410, Washington, DC, 20057, USA. FAU - Jin, Lu AU - Jin L AD - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, The Research Building, Room E410, Washington, DC, 20057, USA. FAU - Fu, Yi AU - Fu Y AD - The Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University Research Center, Arlington, VA, USA. FAU - Cheng, Zuolin AU - Cheng Z AD - The Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University Research Center, Arlington, VA, USA. FAU - Wang, Yue AU - Wang Y AD - The Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University Research Center, Arlington, VA, USA. FAU - de Assis, Sonia AU - de Assis S AUID- ORCID: 0000-0001-5053-0614 AD - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, The Research Building, Room E410, Washington, DC, 20057, USA. deassiss@georgetown.edu. LA - eng GR - 1P30-CA51008/CA/NCI NIH HHS/United States GR - TL1 TR001431/TR/NCATS NIH HHS/United States GR - P30 CA051008/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180830 PL - England TA - Breast Cancer Res JT - Breast cancer research : BCR JID - 100927353 RN - 0 (3-(2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino)-2-thioxoimidazolidin-4-one on 7,12-dimethylbenz(a)anthracene) RN - 0 (Anthracenes) RN - 0 (MicroRNAs) RN - 0 (Piperidines) SB - IM MH - Animals MH - Animals, Newborn MH - Anthracenes/toxicity MH - *Birth Weight MH - Cell Transformation, Neoplastic/genetics/*metabolism MH - Diet, Protein-Restricted/adverse effects MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Incidence MH - Male MH - Malnutrition/etiology/*metabolism MH - Mammary Glands, Animal/metabolism/pathology MH - Mammary Neoplasms, Experimental/chemically induced/*epidemiology/genetics/pathology MH - Metabolic Networks and Pathways MH - Mice MH - Mice, Inbred C57BL MH - MicroRNAs/genetics/metabolism MH - Paternal Exposure/*adverse effects MH - Piperidines/toxicity MH - Pregnancy MH - Risk Assessment PMC - PMC6117960 OTO - NOTNLM OT - AMPK pathway OT - Ancestral nutrition OT - Breast cancer OT - Paternal programming COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All animal procedures were approved by the Georgetown University Animal Care and Use Committee (protocol #2016-1172), and the experiments were performed following the National Institutes of Health guidelines for the proper and humane use of animals in biomedical research. This study makes use of human data generated by TCGA Research Network (http://cancergenome.nih.gov/). CONSENT FOR PUBLICATION: All authors approved of the manuscript and consent to its publication. COMPETING INTERESTS: The authors declare that they no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/09/01 06:00 MHDA- 2019/05/23 06:00 PMCR- 2018/08/30 CRDT- 2018/09/01 06:00 PHST- 2017/10/23 00:00 [received] PHST- 2018/07/31 00:00 [accepted] PHST- 2018/09/01 06:00 [entrez] PHST- 2018/09/01 06:00 [pubmed] PHST- 2019/05/23 06:00 [medline] PHST- 2018/08/30 00:00 [pmc-release] AID - 10.1186/s13058-018-1034-7 [pii] AID - 1034 [pii] AID - 10.1186/s13058-018-1034-7 [doi] PST - epublish SO - Breast Cancer Res. 2018 Aug 30;20(1):99. doi: 10.1186/s13058-018-1034-7.