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Daughters of obese mouse dads risk breast cancer

Obese male mice and normal weight female mice produce female pups that are overweight at birth and throughout childhood, have delayed development of their breast tissue, and have increased rates of breast cancer.


This is one of the first animal studies to examine the impact of paternal obesity on future generations' cancer risk. The findings by Georgetown Lombardi Comprehensive Cancer Center are published in the June 24 issue of Scientific Reports.


Researchers believe they have evidence that obesity changes microRNA (miRNA) signatures — epigenetic regulators of gene function — in both dad's sperm and daughter's breast tissue. This suggests miRNAs carry epigenetic obesity signals from dad to daughters.

The miRNAs identified regulate insulin signaling, linked to alterations in body weight and molecular pathways associated with cancer development such as the hypoxia signaling pathway.


Obesity seems to run in families, as do some breast cancers. Maternal obesity is believed to influence both in humans — a woman who is heavy in pregnancy can produce large babies who may have increased risk of breast cancer later in life. While much of the focus has been on the mom, few if any studies look at the influence of dad's obesity on his offspring's cancer risk.

The influence of epigenetics (changes derived from non-genetic influences) is highest in early embryonic development. The risk of several chronic diseases in adulthood are thought to result from environmental exposures in early life.

In mammals, epigenetic information is known to be transmitted from one generation to another through the egg and sperm (germ cells). Germ cells can and do carry environmental epigenetic memory from previous generations. This plasticity of interpretting genetic code allows us to adapt more quickly to enviornmental changes.

Epigenetic information in cells is carried via three different mechanisms:
(1) DNA methylation — signaling tool that can fix genes in the “off” position (2) histone modifications — which loosens or tightens chromatin structure
(3) non-coding RNAs — an RNA molecule not translated into a protein

These cellular machineries regulate how genes are expressed (turned off and on) affecting how cells differentiate during development and throughout life.


"This study provides evidence that, in animals, a fathers' body weight at the time of conception affects both their daughters' body weight both at birth and in childhood as well as their risk of breast cancer later in life.

"Of course our study was done in mice, but it recapitulates recent findings in humans which show obese men have significant epigenetic alterations in their sperm compared to lean men. Our animal study suggests those epigenetic alterations in sperm may have consequences for next generation cancer risk."


Sonia de Assis PhD, Assistant Professor, Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington D.C. USA; and lead investigator.


The next step in this research is to see if the same associations regarding breast cancer risk hold for daughters of human fathers who are overweight around the time of conception.

Sonia de Assis: "Until we know about this association in men, we should stick to what we all know is good advice: women — and men — should eat a balanced diet, keep a healthy body weight and life-style not only for their own benefit but also to give their offspring's the best chances of being healthy."

Abstract
While many studies have shown that maternal weight and nutrition in pregnancy affects offspring’s breast cancer risk, no studies have investigated the impact of paternal body weight on daughters’ risk of this disease. Here, we show that diet-induced paternal overweight around the time of conception can epigenetically reprogram father’s germ-line and modulate their daughters’ birth weight and likelihood of developing breast cancer, using a mouse model. Increased body weight was associated with changes in the miRNA expression profile in paternal sperm. Daughters of overweight fathers had higher rates of carcinogen-induced mammary tumors which were associated with delayed mammary gland development and alterations in mammary miRNA expression. The hypoxia signaling pathway, targeted by miRNAs down-regulated in daughters of overweight fathers, was activated in their mammary tissues and tumors. This study provides evidence that paternal peri-conceptional body weight may affect daughters’ mammary development and breast cancer risk and warrants further studies in other animal models and humans.

Other researchers involved in this study include Camile Fontelles, Elissa Carney, Johan Clarke, Nguyen M. Nguyen, Chao Yin, Idalia Cruz, Lu Jin, Leena Hilakivi-Clarke and Thomas Ong.

American Cancer Society and the Prevent Cancer Foundation funded the study.

About Georgetown Lombardi Comprehensive Cancer Center
Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and MedStar Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Georgetown Lombardi is one of only 46 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington, DC, area. For more information, go to http://lombardi.georgetown.edu.

About Georgetown University Medical Center
Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health.
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Jun 29, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



Sonia de Assis: "Until we know about this association in men, we should stick to what we all know is good advice: women — and men — should eat a balanced diet, keep a healthy body weight and life-style not only for their own benefit but also to give their offspring's the best chances of being healthy."
Image Credit: Wikipedia.org


 


 

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