|Rahal, Omar -|
|Pabona, John Mark -|
|Kelly, Thomas -|
|Haung, Yan -|
|Hennings, Leah -|
|Prior, Ronald -|
|Al-Dwairi, Ahmed -|
|Simmen, Frank -|
|Simmen, Rosalia -|
Submitted to: Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 31, 2012
Publication Date: February 15, 2013
Citation: Rahal, O., Pabona, J.P., Kelly, T., Haung, Y., Hennings, L.J., Prior, R.L., Al-Dwairi, A., Simmen, F.A., Simmen, R.C. 2013. Suppression of wnt1-induced mammary tumor growth and lower serum insulin in offspring exposed to maternal blueberry diet suggest early dietary influence on developmental programming. Carcinogenesis. 34(2):464-474. Interpretive Summary: Breast cancer risk in adults can be modified by exposure to certain environmental factors such as diet during early stages of life such as occurs in the fetus during pregnancy and/or with breast feeding. In the present study we evaluated the effect of blueberry feeding during pregnancy and lactation on breast cancer in the offspring. We showed that maternal blueberry diet protects mice against breast cancer development by up-regulation of growth suppressor proteins and hormones that are associated with obesity and inflammation. Our findings provide important evidence for role of early dietary intervention to prevent adult onset of breast cancer.
Technical Abstract: Despite the well-accepted notion that early maternal influences persist beyond fetal life and may underlie many adult diseases, the risks imposed by the maternal environment on breast cancer development and underlying biological mechanisms remain poorly understood. Here, we investigated whether early exposure to blueberry [BB] via maternal diet alters oncogene Wnt1-induced mammary tumorigenesis in offspring. Wnt1-transgenic female mice were exposed to maternal Casein [CAS, control] or blueberry-supplemented [CAS+3%BB] diets throughout pregnancy and lactation. Offspring were weaned to CAS, and mammary tumor development was followed until age 8 months. Tumor incidence and latency were similar for both groups; however, tumor weight at sacrifice and tumor volume within 2 weeks of initial detection were lower (by 50% and 60%, respectively) in offspring of BB- versus control-fed dams. Dietary BB exposure beginning at weaning did not alter mammary tumor parameters. Tumors from maternal BB-exposed offspring showed higher tumor suppressor (Pten, Cdh1) and lower pro-proliferative (Ccnd1), anti-apoptotic (Bcl2), and pro-angiogenic (Figf, Flt1, Ephb4) transcript levels, and displayed attenuated microvessel density. Expression of Pten and Cdh1 genes was also higher in mammary tissues of maternal BB-exposed offspring. Mammary tissues and tumors of maternal BB-exposed offspring showed increased chromatin-modifying enzyme Dnmt1 and Ezh2 transcript levels. Body weight, serum insulin and serum leptin/adiponectin ratio were lower for maternal BB-exposed than control tumor-bearing offspring. Tumor weights and serum insulin were positively correlated. Results suggest that dietary influences on the maternal environment contribute to key developmental programs in the mammary gland to modify breast cancer outcome in adult progeny.