Exploring ovarian-derived hormone STC1 as the mediator of the protective effect of breast feeding against breast cancer.

怀孕会给乳房带来显著的变化；1--怀孕期间，令人印象深刻的细胞增殖 并观察到导管树的分化，2-哺乳期，乳房的终极功能，3-哺乳期 哺乳期后退缩与组织重塑和炎症有关。有趣的是，这两个 妊娠期的增殖和退化期的炎症参与了与以下相关的信号通路 而且，怀孕后患乳腺癌的风险也会增加。然而，延长哺乳时间 降低这种风险，但母乳喂养保护作用的分子机制尚不清楚。基座 根据我们的初步数据，我们假设卵巢衍生荷尔蒙锡钙素1(STC1)是潜在的 母乳喂养保护作用的中介物。STC-1是一种主要由卵巢分泌的激素。 在哺乳期间。已发现它是妊娠相关血浆中PAPP-A酶的抑制因子 蛋白A.Papp-A是一种分泌型蛋白酶，通过降解IGFBP-A，通过IGF信号转导促进增殖。 5在退化过程中，促进免疫逃避，我们报告利用了 内陷以促进转移。PAPP-A在乳腺癌中经常过度表达，我们有 创造了第一个PAPP-A驱动的乳腺肿瘤的小鼠模型。对于这个应用程序来说，重要的是，我们发现 这种长时间的哺乳可以防止PAPP-A驱动的肿瘤的形成。我们的假设是卵巢来源的STC1 在哺乳过程中产生的物质通过循环到达乳腺，饱和并抑制PAPP-A和 是长时间哺乳保护作用的机制。我们给出的初步数据是 PAPP-A与来自哺乳期雌性而不是非哺乳期雌性的血清孵育， 抑制其降解IGFBP-5的能力。此外，从哺乳期女性血清块中耗尽STC1 这种效果。这个探索性奖项的目标是测试从哺乳期献血者输血到非 产后退缩期间的哺乳接受者可以模仿哺乳的保护作用。 女性。为了测试这种可能性，我们提出了以下目标：具体目标1：表征潜力 哺乳过程中血清STC1浓度和活性的变化并确定是否输血 从哺乳期雌性小鼠的血液中提取乳汁可以模拟野生型非哺乳期小鼠长时间哺乳的保护作用。 特异性目的2：检测卵巢STC1对PAPP-A诱导的乳腺肿瘤的保护作用。在这 目的，我们将执行与目标1中描述的相同实验，但在MMTV-PAPP-A转基因小鼠中 例外情况。首先，由于这个模型比没有事先哺乳的正常退缩更具侵略性，我们 将使用更密集的输血计划。其次，由于75%的PAPP-A转基因小鼠是后天发育的 产期乳房肿瘤当女性不分泌乳汁时，我们会监测肿瘤的形成。

Pregnancy imposes remarkable changes to the breast; 1- during pregnancy, impressive cellular proliferation and differentiation of the ductal tree is observed, 2- during lactation, the ultimate function of breast and 3- during post-lactation involution that is associated with tissue remodeling and inflammation. Interestingly both the proliferation during pregnancy and the inflammation during involution engage signaling pathways associated with cancer and indeed, the risk of breast cancer increases following pregnancy. However, extended lactation reduces that risk but the molecular mechanism of the protective effect of breastfeeding remains unknown. Based on our preliminary data, we postulate that the ovarian-derived hormone stanniocalcin 1 (STC1) is the potential mediator of the protective effect of breastfeeding. STC 1 is a secreted hormone produced mainly by the ovaries during lactation. It has been found to act as an inhibitor of the protease PAPP-A, Pregnancy-Associated Plasma Protein A. PAPP-A is a secreted protease that promotes proliferation through IGF signaling by degrading IGFBP- 5 during involution, promotes immune evasion and we reported takes advantage of the microenvironment of involution to promote metastasis. PAPP-A is frequently overexpressed in the breast cancers and we have generated the first mouse model of PAPP-A driven mammary tumors. Importantly for this application, we found that long lactation prevents the formation of PAPP-A-driven tumors. Our hypothesis is that ovarian-derived STC1 produced during lactation reach the mammary gland through the circulation, saturates and inhibits PAPP-A and is the mechanism underlying the protective effect of long lactation. We present preliminary data that incubation of PAPP-A with serum taken from lactating females, but not from non-lactating females, inhibits its ability to degrade IGFBP-5. Further, depletion of STC1 from lactating -female serum blocks this effect. The goal of this exploratory award is to test if transfusions of blood from lactating donors into non- lactating recipients during post-partum involution, can mimic the protective effect of lactation in these recipient females. In order to test this possibility, we propose the following aims; Specific aim 1: Characterize potential fluctuations in the serum concentration and activity of STC1 throughout lactation and determine if transfusions of blood from lactating females can mimic the protective effect of long lactation in wild-type non-lactating mice. Specific aim 2: Testing the protective effect of ovarian STC1 against PAPP-A driven mammary tumors. In this aim, we will perform the same experiment described in aim 1 but in the MMTV-PAPP-A transgenic mice with two exceptions. First, since this model is much more aggressive than normal involution without prior lactation, we will use a more intense scheduling of transfusions. Second, since 75% of PAPP-A transgenic mice develop post- partum mammary tumors when females do not lactate, we will monitor tumor formation.