Pregnancy Estrogens, Diet, and Breast Cancer Risk

妊娠期雌激素水平升高50-100倍，妊娠期雌激素水平的个体差异为4-6倍。研究表明，孕期雌激素水平较高的女性患乳腺癌的风险显著增加，这可能是由于雌激素促进了现有转化细胞。饮食，尤其是饮食中的脂肪，可能会影响孕期雌激素水平和后来患乳腺癌的风险。在我们的动物研究中，高脂肪摄入显著增加了妊娠雌激素水平，增加了妊娠促进的乳腺肿瘤发病率。雌激素代谢基因的多态性与乳腺癌风险增加有关，也可能影响妊娠期雌激素水平。我们提出的研究有两个总体目的：(1)研究膳食脂肪摄入是否会影响女性妊娠雌激素水平，可能是通过与CYP17和COMT多态性的相互作用；(2)研究妊娠雌激素水平高是否会通过增加生长因子水平增加乳腺癌风险。这些生长因子可能来源于突变或已经转化的乳腺细胞，这些细胞在怀孕期间受到高雌激素水平的刺激。生长因子水平将在乳头抽吸液（NAF）中测量，可以使用吸乳器从非泌乳乳房中获得。因此，以下假设将被检验：假设1。我们假设高脂肪摄入和体重增加会增加孕期雌激素水平。我们进一步假设CYP17或COMT的多态性影响这些相互作用。假设二则。我们假设怀孕期间较高的循环雌二醇水平与乳头吸出液中生长因子水平的增加有关，包括EGF、TGFalpha和IGF-1/IGF结合蛋白3。这些目标将在NAF索尔纳产科诊所的200名孕妇中进行研究，这些孕妇将在分娩后12个月获得。我们的研究结果可能会导致改变孕期饮食以降低患乳腺癌的风险。特别是，由于乳腺癌家族史、首次怀孕年龄（超过30岁）或其他生殖风险因素而已经处于高风险的妇女，可能会从孕期饮食调整中显著受益。

Estrogen levels are elevated by 50-100 -fold during pregnancy, and inter-individual variability in pregnancy estrogen levels is 4-6 -fold. Women exhibiting highest pregnancy estrogen levels are suggested to be at a significantly increased risk to develop breast cancer, perhaps due to an estrogen-induced promotion of existing transformed cells. Diet, particularly dietary fats, may affect pregnancy estrogen levels and later breast cancer risk. In our animal study, a high fat intake significantly increased pregnancy estrogen levels and increased pregnancy-promoted mammary tumor incidence. Polymorphism in genes that metabolize estrogens and have been linked to increased breast cancer risk, may also affect pregnancy estrogen levels. Our proposed study has two general aims: (1) to study whether dietary fat intake affects pregnancy estrogen levels in women, perhaps by interacting with polymorphism in CYP17 and COMT, and (2) to study whether highest pregnancy estrogen levels might increase breast cancer risk by increasing growth factor levels. These growth factors could originate from mutated or already transformed mammary cells, which during pregnancy are stimulated by high estrogen levels. Growth factor levels will be measured in nipple aspirate fluid (NAF) that can be obtained using a breast pump from non-lactating breast. Consequently, the following hypotheses will be tested: Hypothesis-1. We hypothesize that high dietary fat intake and weight gain increase pregnancy estrogen levels. We further hypothesize that polymorphism in CYP17 or COMT influences these interactions. Hypothesis-2. We hypothesize that higher circulating estradiol levels during pregnancy are associated with increased growth factor levels in nipple aspirate fluid, including EGF, TGFalpha and IGF-1/IGF binding protein 3. These aims will be studied in 200 pregnant women attending the Maternity Clinic at Solna in NAF will be obtained 12 months after giving birth. Our results may lead to modifications of pregnancy diet to reduce the risk to develop breast cancer. In particular, women who already are at high risk, for example, due to family history of breast cancer, age at first pregnancy (greater than 30 years), or other reproductive risk factors, may significantly benefit from pregnancy dietary modifications.