Pre‐ and postpubertal irradiation induces mammary cancers with distinct expression of hormone receptors, ErbB ligands, and developmental genes in rats

Abstract

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-wk-old, respectively) female Sprague-Dawley rats were whole-body γ-irradiated (2 Gy), injected intraperitoneally with MNU (20 mg/kg) or left untreated and were autopsied at 50 wk of age. Mammary carcinomas were examined for estrogen receptor (ER) α, 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 ERα 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.

Exposure to Ionizing Radiation Causes Long-Term Increase in Serum Estradiol and Activation of PI3K-Akt Signaling Pathway in Mouse Mammary Gland

“…Importantly, our results do not rule out the possibility that radiation exposure might also positively alter the hypothalamic–pituitary axis to enhance estrogen biosynthesis and release. Although exogenous estrogen has been shown to act synergistically in radiation-related mammary carcinogenesis, and radiation has been shown to induce ERα in rats (5, 17), here we show, for the first time to our knowledge, that radiation exposure led to sustained elevated level of endogenous estradiol at 2 months and 12 months in mice, with implications for carcinogenesis.…”

Cancer prevention by adult‐onset calorie restriction after infant exposure to ionizing radiation in B6C3F1 male mice

“…The B6C3F1 male mouse model used in this study is limited in its ability to assess the cancer risks of other radio‐susceptible tissues such as breast and colon. This limitation will be overcome, in part, by utilizing models for radiation‐induced mammary tumors in rats and colon tumors in Apc Min/+ mice . CR is reported to inhibit radiation‐induced rat sarcomas including mammary tumors .…”

Prognosis, stage and oestrogen receptor status of contralateral breast cancer in relation to characteristics of the first tumour, prior endocrine treatment and radiotherapy

“…This is supported by preclinical studies showing radiotherapy to reduce ER-expression in breast cancer cell-lines and rat mammary-tumors (22)(23)(24)(25), as well as to induce ER-negative breast cancer in premenopausal mice (26). Potential explanations could be: Activation of DNA-repair pathways influencing ER-expression (23); Disturbance of ERautoregulation involving micoRNA (27,28); Microenvironmental changes inducing an ERnegative stem-cell-enriched phenotype (29); and promoter-hypermethylation reducing estrogen binding-affinity and signaling (25,28).…”