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.

怀孕对乳房施加了显着的变化。 1-怀孕期间，令人印象深刻的细胞增殖 观察到导管树的分化，2-在哺乳期间，乳房的最终功能，3-在 与组织重塑和炎症相关的隔离后相互作用。有趣的是 怀孕期间的增殖和互动期间的炎症参与信号通路 癌症，实际上，怀孕后乳腺癌的风险增加。但是，延长泌乳 降低了这种风险，但是母乳喂养保护作用的分子机制仍然未知。基于 在我们的初步数据上，我们假设卵巢衍生的激素Stanniocalcin 1（STC1）是潜力 母乳喂养保护作用的介体。 STC 1是一种分泌的激素，主要由卵巢产生 在哺乳期间。已经发现它是蛋白酶PAPP-A，与妊娠相关血浆的抑制剂 蛋白A. PAPP-A是一种分泌的蛋白酶，通过降解IGFBP-通过IGF信号传导促进增殖 5在互动期间，促进免疫逃避，我们报告利用了微环境的优势 促进转移的互动。 PAPP-A经常在乳腺癌中过表达，我们有 生成了PAPP-A驱动乳腺肿瘤的第一个小鼠模型。重要的是，对于此应用程序，我们发现 长泌乳阻止了PAPP-A驱动肿瘤的形成。我们的假设是卵巢衍生的STC1 泌乳期间产生的通过循环到达乳腺，饱和并抑制PAPP-A，并且 是长泌乳的保护作用的基础机制。我们提供初步数据 将PAPP-A与哺乳动物的血清一起孵育，而不是从非乳酸女性中孵育 抑制其降解IGFBP-5的能力。此外，从泌乳 - female -Female血清块中耗尽了STC1 这个效果。该探索性奖励的目的是测试是否会从泌乳供体中输血到非 - 产后相互作用期间的哺乳接受者可以模仿这些接受者泌乳的保护作用 女性。为了测试这种可能性，我们提出以下目标；特定目标1：表征潜力 整个泌乳过程中STC1的血清浓度和活性的波动，并确定输血是否 哺乳性雌性的血液可以模仿野生型非乳酸小鼠的长泌乳的保护作用。 具体目标2：测试卵巢STC1对PAPP-A驱动乳腺肿瘤的保护作用。在这个 AIM，我们将执行AIM 1中描述的相同实验，但在MMTV-PAPP-A转基因小鼠中 例外。首先，由于没有事先泌乳的情况比正常情况要比正常情况更具攻击性，因此我们 将使用更激烈的输血计划。其次，由于75％的PAPP-A转基因小鼠在 乳腺肿瘤不乳酸时，我们将监测肿瘤的形成。