Liu Yiliang E, Pu Weiping, Wang Jingdong, Kang Jing X, Shi Y Eric
Feinstein Institute for Medical Research, Department of Radiation Oncology, Long Island Jewish Medical Center, The Albert Einstein College of Medicine, New Hyde Park, NY 11040, USA.
FEBS J. 2007 Jul;274(13):3351-62. doi: 10.1111/j.1742-4658.2007.05869.x. Epub 2007 Jun 5.
The protective effect of early pregnancy against breast cancer can be attributed to the transition from undifferentiated cells in the nulliparous to the differentiated mature cells during pregnancy. Considerable evidence suggests strongly that the n-3 polyunsaturated fatty acid (PUFA) content of adipose breast tissue is inversely associated with an increased risk of breast cancer. Here, we report that there was a decrease in the n-6/n-3 PUFA ratio and a significant increase in concentration of n-3 PUFA docosapentaenoic acid and eicosapentaenoic acid in the pregnant gland. The functional role of n-3 PUFAs on differentiation was supported by the studies in the fat-1 transgenic mouse, which converts endogenous n-6 to n-3 PUFAs. Alternation of the n-6/n-3 ratio in favor of n-3 PUFA, and particularly docosapentaenoic acid, in the mammary gland of fat-1 mouse resulted in development of lobulo-alveolar-like structure and milk protein beta-casein expression, mimicking the differentiated state of the pregnant gland. Docosapentaenoic acid and eicosapentaenoic acid activated the Jak2/Stat5 signaling pathway and induced a functional differentiation with production of beta-casein. Expression of brain type fatty acid binding protein brain type fatty acid binding protein in virgin transgenic mice also resulted in a reduced ratio of n-6/n-3 PUFA, a robust increase in docosapentaenoic acid accumulation, and mammary differentiation. These data indicate a role of mammary derived growth inhibitor related gene for preferential accumulation of n-3 docosapentaenoic acid and eicosapentaenoic acid in the differentiated gland during pregnancy. Thus, alternation of n-6/n-3 fatty acid compositional ratio in favor of n-3 PUFA, and particularly docosapentaenoic acid and eicosapentaenoic acid, is one of the underlying mechanisms of pregnancy-induced mammary differentiation.
早期妊娠对乳腺癌的保护作用可归因于孕期未生育女性乳房中未分化细胞向分化成熟细胞的转变。大量证据有力表明，乳腺脂肪组织中n-3多不饱和脂肪酸（PUFA）含量与乳腺癌风险增加呈负相关。在此，我们报告，孕期乳腺中n-6/n-3 PUFA比值降低，n-3 PUFA二十二碳五烯酸和二十碳五烯酸浓度显著增加。在fat-1转基因小鼠（可将内源性n-6转化为n-3 PUFA）中的研究支持了n-3 PUFAs在分化中的功能作用。fat-1小鼠乳腺中n-6/n-3比值向有利于n-3 PUFA（特别是二十二碳五烯酸）的方向改变，导致小叶-腺泡样结构发育和乳蛋白β-酪蛋白表达，模拟了孕期乳腺的分化状态。二十二碳五烯酸和二十碳五烯酸激活Jak2/Stat5信号通路并诱导β-酪蛋白产生的功能分化。初情期转基因小鼠中脑型脂肪酸结合蛋白的表达也导致n-6/n-3 PUFA比值降低、二十二碳五烯酸积累显著增加以及乳腺分化。这些数据表明乳腺衍生生长抑制相关基因在孕期分化乳腺中对n-3二十二碳五烯酸和二十碳五烯酸优先积累的作用。因此，n-6/n-3脂肪酸组成比例向有利于n-3 PUFA（特别是二十二碳五烯酸和二十碳五烯酸）的方向改变是孕期诱导乳腺分化的潜在机制之一。
