Pre- and Postpubertal Irradiation Induces Mammary Cancers with Distinct Expression of Hormone Receptors, ErbB Ligands and Developmental Genes in Rats.

Childhood exposure to carcinogens renders a higher risk of breast cancer. The molecular mechanisms underlying cancer development after such exposure are not, however, well understood. Here we examined how the mechanism of cancer development relates to the age at exposure to ionizing radiation (IR) or the carcinogen 1-methyl-1-nitrosourea (MNU). Pre- and postpubertal (3- and 7-week-old, respectively) female Sprague-Dawley rats were whole-body gamma-irradiated (2 Gy), injected intraperitoneally with MNU (20 mg/kg) or left untreated and were autopsied at 50 weeks of age. Mammary carcinomas were examined for estrogen receptor (ER) alpha, progesterone receptor (PR) and ErbB ligand expression and for expression microarrays. Early histological changes of the ovaries were also evaluated. The incidence of mammary cancer was higher after postpubertal, rather than prepubertal, IR exposure; the inverse was true for MNU. Most cancers were positive for both ERalpha and PR except for the prepubertal IR group. Cancers of the prepubertal IR group expressed a different set of ErbB ligands from those of the other groups and did not overexpress Areg, which encodes an estrogen-regulated ErbB ligand, or other developmentally related genes including those for hormonally regulated mammary gland development. Prepubertal IR exposure resulted in ovarian dysfunction as revealed by a reduced follicular pool. Evidence thus suggests that mammary carcinogenesis induced by prepubertal IR exposure is independent of ovarian hormones but requires certain ErbB ligands; induction by postpubertal exposure depends on ovarian hormones and different ErbB ligands. In contrast, the mechanism of MNU-induced carcinogenesis was less influenced by the age at exposure