Nutrition and fetal origin of breast cancer: effect of zinc deficiency or supplementation during gestational phase of mice on offspring\'s susceptibility to mammary carcinogenesis

Author(s)

Raquel Santana da Cruz

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2016-01-21

Examining board members

Thomas Prates Ong; Fernando Salvador Moreno; Ana Lydia Sawaya

• Advisor: Thomas Prates Ong

Abstract

Breast cancer is an important public health problem, representing the main cause of women death worldwide. Dietetic factors, such as omega-3 fatty-acids, flavonoids, vitamins A and E, and micronutrients have been associated with the reduction of breast cancer risk. Zinc is a micronutrient of remarkable importance for health, essential for several cellular mechanisms, which may influence the development of breast cancer through epigenetic mechanisms, among others. A hypothesis not frequently addressed in the literature, although biologically plausible, considers the fetal origin of breast cancer, a developmental stage in which the mammary gland would be more sensitive to the influence of maternal diet and hormone levels. The maternal diet during pregnancy seems to have significant influence in the modulation of the intrauterine environment and, consequently, in programming the risk of development of breast cancer in offspring through the induction of morphological and molecular changes. The inadequate modulation of the epigenome in early life may have implications for the offspring throughout life, modulating the susceptibility to the risk of chronic diseases, including breast cancer. The exposure during the fetal period, to zinc, seems also to modulate the susceptibility to the development of chronic diseases, such as cardiovascular diseases and renal dysfunctions. Thereby, it would be interesting to evaluate the effects of zinc deficiency or supplementation in maternal diet during pregnancy period in the susceptibility of breast cancer in offspring. In this context, we propose to evaluate if zinc is a dietary factor that may modify the risk of breast cancer during early life, by modulation of morphological, molecular and epigenetic events. C57BL/6 female mice consumed during pregnancy control diet (AIN-93G; CO group); zinc-deficient diet (8 ppm; ZnD group) and zinc-supplemented diet (45 ppm; ZnS group). Mammary tumors were induced by subcutaneous administration of 15mg of medroxyprogesterone to 6-week-old female offspring, followed by oral administration of 1mg 7, 12-dimethylbenz[a]anthracene once-a-week for 4 weeks. Non-initiated mammary glands of 7-week-old female offspring from all groups were used to morphological, cell proliferation, apoptosis and molecular analysis. Compared to CO group offspring, ZnS presented increased (p<0.05) mammary tumor incidence, cell proliferation (Ki67) and apoptosis. Expression levels of p21 protein was higher (p=0.06) in ZnS compared to the CO group. Compared to ZnD group offspring, ZnS showed higher (p<0.05) expression level of p53 protein. There were no differences (p&#8805;0.05) concerning these variables between CO and ZnD group. Compared to CO offspring group, ZnS also showed marginal increased (p=0.08) expression of RASSF1 and STAT3 genes. Compared to ZnD offspring group, ZnS showed higher (p=0.02) expression of ZPF382. H3K9me3 and H4K20me3 were upregulated (p<0.05) in the mammary gland of ZnD female offspring compared to CO and ZnS groups. Thereby, zinc-supplementation, but not zinc-deficiency, in early-life was associated with an increased susceptibility to breast cancer development in adulthood. (AU)

• FAPESP's process: 13/04960-9 - Nutrition and fetal origin of breast cancer: effect of zinc deficiency or supplementation during gestational phase of mice on offspring's susceptibility to mammary carcinogenesis
• Grantee: Raquel Santana da Cruz
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)