Persistent parity-induced changes in growth factors, TGF-β3, and differentiation in the rodent mammary gland
Persistent parity-induced changes in growth factors, TGF-β3, and differentiation in the rodent mammary gland
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DOI：
10.1210/me.2002-0073
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发表时间：
2002-09-01
影响因子：
--
通讯作者：
Chodosh, LA
中科院分区：
文献类型：
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作者：
D'Cruz, CM;Moody, SE;Chodosh, LA
流行病学研究多次表明，首次足月妊娠早期的女性一生患乳腺癌的风险显着降低。同样，与年龄匹配的未生育对照相比，先前经历过足月妊娠的啮齿动物对致癌物诱发的乳腺癌具有高度抵抗力。然而，在理解这种现象的生物学基础方面进展甚微。我们使用 DNA 微阵列鉴定了一组 38 个差异表达基因，这些基因以盲法可重复地区分多种小鼠和大鼠品系的乳腺未产和已产状态。我们发现，奇偶性导致多个编码生长因子的基因持续下调，例如双调蛋白、多效蛋白和 IGF-1，以及生长抑制分子 TGF-β3 及其几个转录靶标的持续上调。我们的研究进一步表明，胎次会导致乳腺分化状态的持续增加以及腺体内造血细胞类型的终生变化。这些发现定义了乳腺难以致癌的发育状态，并为胎次调节乳腺癌风险的机制提出了新的假设。
Epidemiological studies have repeatedly demonstrated that women who undergo an early first fullterm pregnancy have a significantly reduced lifetime risk of breast cancer. Similarly, rodents that have previously undergone a full-term pregnancy are highly resistant to carcinogen-induced breast cancer compared with age-matched nulliparous controls. Little progress has been made, however, toward understanding the biological basis of this phenomenon. We have used DNA microarrays to identify a panel of 38 differentially expressed genes that reproducibly distinguishes, in a blinded manner, between the nulliparous and parous states of the mammary gland in multiple strains of mice and rats. We find that parity results in the persistent down-regulation of multiple genes encoding growth factors, such as amphiregulin, pleiotrophin, and IGF-1, as well as the persistent up-regulation of the growth-inhibitory molecule, TGF-beta3, and several of its transcriptional targets. Our studies further indicate that parity results in a persistent increase in the differentiated state of the mammary gland as well as lifelong changes in the hematopoietic cell types resident within the gland. These findings define a developmental state of the mammary gland that is refractory to carcinogenesis and suggest novel hypotheses for the mechanisms by which parity may modulate breast cancer risk.