Maternal exposure to tamoxifen during pregnancy increases carcinogen- induced mammary tumorigenesis among female rat offspring

Tamoxifen is under investigation as a potential chemopreventive agent in women of child-bearing age who are at an increased risk to develop breast cancer. However, because tamoxifen may act as an estrogen in the fetus and high fetal estrogenic activity, in turn, may increase subsequent breast cancer risk, we wanted to determine the effects of a maternal exposure to tamoxifen during pregnancy on offspring's susceptibility to mammary tumorigenesis. Pregnant rats were injected s.c. with 20 μg of tamoxifen or oil vehicle daily during days 15 and 20 of gestation. In utero exposure to tamoxifen caused abnormalities in the development and function of the reproductive track, including a delayed puberty onset and changes in uterine wet weights. The tamoxifen-exposed offspring, treated with 7,12- dimethylbenz[a]antracene (DMBA) at the age of 45 days, developed an increased incidence of mammary tumors. In week 18 after DMBA administration, 50% of the vehicle-controls had developed mammary tumors, whereas tumor incidence in the tamoxifen group was 95%. In addition, a significantly higher number of tumors in the tamoxifen-exposed group kept growing (rather than stopped growing or regressed) than in the control group. Furthermore, histopathological examination revealed that the mammary tumors in the tamoxifen offspring were less differentiated and exhibited a more aggressive phenotype, compared with the tumors growing in the controls. These results suggest that a maternal exposure to tamoxifen during pregnancy acts as an estrogen in the fetal mammary gland and increases the susceptibility to breast cancer among female offspring.