Effect of prenatal and prepubertal genistein exposure on N-Methyl-N-nitrosourea-induced mammary tumorigenesis in female Sprague-Dawley rats

Background: The effect of prenatal and prepubertal genistein exposure on the development of chemically-induced mammary carcinomas in rat was investigated. Materials and Methods: Genistein was subcutaneously (s.c.) injected daily, from gestational days 15 to 19, into pregnant Sprague-Dawley rats at 0, 1.5 or 30 mg/kg/day. Female offspring of mothers not exposed to genistein during pregnancy received daily s.c. injection, from prepubertal days 15 to 19, at a dose of 1.5 or 30 mg/kg/day. At 28 days of age, 6 female offspringfrom each group were sacrificed to observe the influence of genistein and the remaining rats were injected intraperitoneally with 50 mg/kg N-methyl-N-nitrosourea (MNU). Rats injected with MNU were sacrificed at 26 weeks of age or when their largest mammary tumor was greater than or equal to1 cm in size. Results: At the time when MNU was administered, the different groups had comparable mammary gland development; genistein-treated and -untreated rats had similar numbers of terminal end buds (TEBs) at the periphery of the mammary glandular tree. However, estrogen receptor alpha (ERalpha) - and progesterone receptor (PgR)-positive cells, p63-positive cells and proliferating cell nuclear antigen (PCNA)-labeling index were lower in genistein-exposed TEBs. Although tumor multiplicity and latency were not significant, prenatal or prepubertal genistein exposure, at low or high dosage, tended to suppress the incidence of mammary carcinomas greater than or equal to1 cm,- suppression was significant in the prepubertal low-dose group. Conclusion: The majority of the mammary carcinomas in the present study were hormone-dependent. The present findings suggest that administration of genistein in the perinatal period has protective effects against MNU-induced mammary carcinoma in Sprague-Dawley rats, via reduction of levels of ERalpha- and/or PgR-positive cells (presumed progenitor cells of mammary carcinomas), p63-positive mammary progenitor/stem cells (involved in cell renewal) and PCNA-positive cells (necessary for cell proliferation).