Experimental Radiobiology for Children's Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
Mol Carcinog. 2011 Jul;50(7):539-52. doi: 10.1002/mc.20746. Epub 2011 Mar 3.
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.
儿童时期接触致癌物质会增加患乳腺癌的风险。然而，这种接触后癌症发展的分子机制尚不清楚。在这里，我们研究了癌症发展的机制与暴露于电离辐射（IR）或致癌剂 1-甲基-1-亚硝脲（MNU）的年龄之间的关系。分别在 3 周龄和 7 周龄时对雌性 Sprague-Dawley 大鼠进行全身γ照射（2 Gy）、腹腔内注射 MNU（20 mg/kg）或不处理，并在 50 周龄时进行尸检。检查乳腺癌中雌激素受体（ER）α、孕激素受体（PR）和 ErbB 配体的表达情况，并进行表达微阵列分析。还评估了卵巢的早期组织学变化。与青春期前暴露相比，青春期后暴露 IR 后乳腺癌的发病率更高；而 MNU 则相反。除了青春期前的 IR 组外，大多数癌症均为 ERα 和 PR 阳性。青春期前的 IR 组的癌症表达了一组与其他组不同的 ErbB 配体，并且不表达 Areg（编码受雌激素调节的 ErbB 配体）或其他发育相关基因，包括受激素调节的乳腺发育基因。青春期前的 IR 暴露导致卵泡池减少，从而导致卵巢功能障碍。有证据表明，青春期前 IR 暴露引起的乳腺癌发生不依赖于卵巢激素，但需要某些 ErbB 配体；青春期后暴露的诱导依赖于卵巢激素和不同的 ErbB 配体。相比之下，MNU 诱导的致癌机制受暴露年龄的影响较小。
