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

探索卵巢源性激素 STC1 作为母乳喂养对乳腺癌保护作用的中介。

• 批准号: 10563256
• 负责人: DORIS A GERMAIN
• 金额: $ 19.75万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10563256
• 关键词: Attention; Award; Blood Transfusion; Breast; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Feeding; Cell Proliferation; Child; Circulation; Clinical; Clinical Trials; DDR2 gene; Data; Duct (organ) structure; Exposure to; Female; Future; Goals; Grant; Harvest; Hormone secretion; Hormones; Human; Immune Evasion; Incubated; Inflammation; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor Receptor; Lactation; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediator; Messenger RNA; Modeling; Molecular; Monitor; Mothers; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Oncogenes; Ovarian; Ovary; Peptide Hydrolases; Postpartum Period; Pregnancy; Pregnancy-Associated Plasma Protein-A; Procedures; Proliferating; Proliferation Marker; Protease Inhibitor; Proteins; Reporting; Risk; Role; STC1 gene; STC2 gene; Schedule; Serum; Signal Pathway; Signal Transduction; Testing; Time; Tissues; Transfusion; Transgenic Mice; Translating; Trees; Trust; Wild Type Mouse; Work; design; experimental study; forging; in vitro activity; inhibitor; malignant breast neoplasm; migration; mouse model; overexpression; prevent; protective effect; theories; tumor

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.

怀孕对乳房造成了显着的变化; 1-在怀孕期间，令人印象深刻的细胞增殖 2-哺乳期，乳腺的最终功能; 3-哺乳期， 泌乳后退化，与组织重塑和炎症有关。有趣的是， 妊娠期间的细胞增殖和退化期间的炎症参与与 癌症，事实上，怀孕后患乳腺癌的风险增加。然而， 降低了这种风险，但母乳喂养保护作用的分子机制仍然未知。基于 根据我们的初步数据，我们假设卵巢源性激素斯钙素1（STC 1）是潜在的 母乳喂养的保护作用的调解人。STC 1是一种主要由卵巢分泌的激素 在哺乳期。已发现它作为蛋白酶PAPP-A，妊娠相关血浆的抑制剂 蛋白a PAPP-A是一种分泌型蛋白酶，通过降解IGFBP-1，通过IGF信号传导促进增殖。 5在退化过程中，促进免疫逃避，我们报告利用微环境的优势， 退化促进转移。PAPP-A在乳腺癌中经常过度表达，我们已经发现， 产生了PAPP-A驱动的乳腺肿瘤的第一个小鼠模型。对于这个应用程序，我们发现 长时间哺乳可以防止PAPP-A驱动的肿瘤的形成。我们的假设是，卵巢源性STC 1 在哺乳期产生的通过循环到达乳腺，饱和并抑制PAPP-A， 是长期哺乳保护作用的潜在机制。我们提供的初步数据表明， PAPP-A与取自哺乳期雌性的血清孵育，但不与取自非哺乳期雌性的血清孵育， 抑制其降解IGFBP-5的能力。此外，从哺乳期雌性血清阻断中消耗STC 1 这种效果。这项探索性研究的目的是测试将哺乳期献血者的血液输给非哺乳期献血者的效果。 哺乳受体在产后退化，可以模仿哺乳的保护作用，在这些受体 女性为了验证这种可能性，我们提出了以下目标：具体目标1：表征潜力 在整个哺乳期的血清浓度和STC 1活性的波动，并确定是否输血 哺乳期雌性动物的血液中的抗氧化剂可以模拟野生型非哺乳期小鼠中长哺乳期的保护作用。 具体目标2：测试卵巢STC 1对PAPP-A驱动的乳腺肿瘤的保护作用。在这 为了实现这一目的，我们将进行与目的1中描述的相同的实验，但是在具有两个基因的MMTV-PAPP-A转基因小鼠中， 例外.首先，由于这种模式比没有哺乳的正常退化更具侵略性，我们 将采用更密集的输血计划。第二，由于75%的PAPP-A转基因小鼠发育后， 当女性不泌乳时，我们将监测肿瘤的形成。