Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy
Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy
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DOI：
10.1158/0008-5472.can-05-4235
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Chodosh, Lewis A.
中科院分区：
文献类型：
--
作者：
Blakely, Collin M.;Stoddard, Alexander J.;Chodosh, Lewis A.
早年生育第一个孩子的女性终生患乳腺癌的风险显着降低。其机制尚不清楚。与人类相似，大鼠表现出胎次诱导的针对乳腺肿瘤发生的保护作用。为了探索这种现象的基础，我们发现了妊娠引起的持续性乳腺基因表达变化，这些变化与多种近交系大鼠品系的肿瘤发生保护密切相关。四种近交大鼠品系对致癌物诱导的乳腺肿瘤发生的内在敏感性表现出显着差异，在用妊娠水平的雌二醇和黄体酮治疗后，每种近交大鼠品系均显示出针对甲基亚硝基脲诱导的乳腺肿瘤发生的显着保护作用。这四种品系的经产和未产乳乳腺组织的微阵列表达谱产生了共同的 70 个基因特征。对构成这一特征的基因的检查表明，妊娠引起的乳腺癌风险改变中，转化生长因子-β信号、细胞外基质、双调蛋白表达和生长激素/胰岛素样生长因子 I 轴的改变有关。值得注意的是，相关的分子变化与乳房X线照相密度降低有关，而乳房X线照相密度本身与乳腺癌风险降低密切相关。我们的研究结果表明，激素诱导的针对乳腺肿瘤发生的保护作用在不同的大鼠品系中广泛保守，并定义了与正常发育事件导致的乳腺肿瘤易感性降低密切相关的基因表达特征。鉴于这一特征的保护，这些途径可能有助于妊娠诱导的乳腺癌预防。
Women who have their first child early in life have a substantially lower lifetime risk of breast cancer. The mechanism for this is unknown. Similar to humans, rats exhibit parity-induced protection against mammary tumorigenesis. To explore the basis for this phenomenon, we identified persistent pregnancy-induced changes in mammary gene expression that are tightly associated with protection against tumorigenesis in multiple inbred rat strains. Four inbred rat strains that exhibit marked differences in their intrinsic susceptibilities to carcinogen-induced mammary tumorigenesis were each shown to display significant protection against methylnitrosourea-induced mammary tumorigenesis following treatment with pregnancy levels of estradiol and progesterone. Microarray expression profiling of parous and nulliparous mammary tissue from these four strains yielded a common 70-gene signature. Examination of the genes constituting this signature implicated alterations in transforming growth factor-beta signaling, the extracellular matrix, amphiregulin expression, and the growth hormone/insulin-like growth factor I axis in pregnancy-induced alterations in breast cancer risk. Notably, related molecular changes have been associated with decreased mammographic density, which itself is strongly associated with decreased breast cancer risk. Our findings show that hormone-induced protection against mammary tumorigenesis is widely conserved among divergent rat strains and define a gene expression signature that is tightly correlated with reduced mammary tumor susceptibility as a consequence of a normal developmental event. Given the conservation of this signature, these pathways may contribute to pregnancy-induced protection against breast cancer.