Diet-induced metabolic change induces estrogen-independent allometric mammary growth
Diet-induced metabolic change induces estrogen-independent allometric mammary growth
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DOI：
10.1073/pnas.1210527109
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发表时间：
2012-10-02
影响因子：
11.1
通讯作者：
Hovey, Russell C.
中科院分区：
文献类型：
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作者：
Berryhill, Grace E.;Gloviczki, Julia M.;Hovey, Russell C.
终生乳腺癌风险反映了未解决的早期生活因素组合，包括饮食，体重指数，代谢综合征，肥胖和首次月经年龄。与此同时，人们普遍认为青春期前后乳腺异速生长的开始是雌激素（E）依赖性的。在这里，我们报告了一些与代谢综合征相关的生理变化，在饮食中补充了反式-10，顺式-12异构体的共轭亚油酸导致卵巢无关的异速生长的乳腺导管。这种饮食诱导的生长的E-独立性突出的事实是，它发生在雄性小鼠和药理学抑制E受体功能或E生物合成。用过氧化物酶体增殖物激活受体-γ激动剂罗格列酮抑制代谢表型可消除饮食诱导的乳腺生长。共轭亚油酸的反式-10，顺式-12异构体诱导的乳腺生长过程中高胰岛素血症和胰岛素样生长因子-I受体（IGF-IR）表达增加的作用通过其对IGF-IR功能的药理学抑制作用的逆转得到证实。饮食刺激的导管生长也增加了卵巢切除多瘤病毒中T抗原小鼠的乳腺肿瘤发生。我们的数据表明，饮食诱导的代谢失调，独立于卵巢功能，刺激异速生长的乳腺内通过IGF-IR依赖的机制。
Lifetime breast cancer risk reflects an unresolved combination of early life factors including diet, body mass index, metabolic syndrome, obesity, and age at first menses. In parallel, the onset of allometric growth by the mammary glands around puberty is widely held to be estrogen (E)-dependent. Here we report that several physiological changes associated with metabolic syndrome in response to a diet supplemented with the trans-10, cis-12 isomer of conjugated linoleic acid lead to ovary-independent allometric growth of the mammary ducts. The E-independence of this diet-induced growth was highlighted by the fact that it occurred both in male mice and with pharmacological inhibition of either E receptor function or E biosynthesis. Reversal of the metabolic phenotype with the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone abrogated diet-induced mammary growth. A role for hyperinsulinemia and increased insulin-like growth factor-I receptor (IGF-IR) expression during mammary growth induced by the trans-10, cis-12 isomer of conjugated linoleic acid was confirmed by its reversal upon pharmacological inhibition of IGF-IR function. Diet-stimulated ductal growth also increased mammary tumorigenesis in ovariectomized polyomavirus middle T-antigen mice. Our data demonstrate that diet-induced metabolic dysregulation, independently of ovarian function, stimulates allometric growth within the mammary glands via an IGF-IR-dependent mechanism.