Role of prolactin in adipocyte-breast cancer cell crosstalk

催乳素在脂肪细胞-乳腺癌细胞串扰中的作用

基本信息

批准号：
10358133
负责人：
MARIA DIAKONOVA
金额：
$ 45.15万
依托单位：
UNIVERSITY OF TOLEDO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10358133
关键词：
Adipocytes Adipose tissue Affect Agonist Androgens Aromatase Biological Markers Breast Breast Cancer Cell Breast Cancer Risk Factor Breast Cancer cell line Breast Carcinoma Breast biopsy Cancer Cell Growth Cancer Prognosis Cell physiology Cells Clinical Research Data Development Endocrine Estrogens Etiology Goals Grant Growth Growth Factor Health Hormones Human Incidence Interleukin-6 Interstitial Collagenase JAK2 gene Knowledge Leptin Link Lipids Malignant Epithelial Cell Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Maps Mediating Metabolic Metabolism Mission Molecular Molecular Target Neoplasm Metastasis Obesity Outcome PAK-1 kinase Pathway interactions Patients Phospho-Specific Antibodies Phosphorylation Pituitary Gland Postmenopause Process Prolactin Public Health Regulation Research Resistance Risk Role Sampling Serine Signal Pathway Signal Transduction System TEC Protein Tyrosine Kinase TNF gene Testing Threonine Tissues Tumorigenicity Tyrosine United States National Institutes of Health Work adipokines adiponectin base breast cancer diagnosis cancer cell cell motility diagnostic biomarker diagnostic tool epidemiology study fatty acid oxidation hormone therapy in vivo innovation insight malignant breast neoplasm mammary migration neoplastic cell new therapeutic target novel novel diagnostics paracrine response stromelysin 3 therapy resistant tool tumor tumor behavior tumor growth tumor microenvironment

项目摘要

Project Summary/Abstract There is a gap in our understanding of how hormone prolactin (PRL), secreted by adipocytes, and the serine/threonine PAK1 connect to coordinately regulate progression of human breast cancer (BC) and adipocyte-breast cancer cell crosstalk. The long-term goal of this research is to establish PAK1, activated by adipocyte-secreted PRL, as a new diagnostic tool for the metastatic potential of BC cells and provide needed insight into the underlying mechanisms. The overall objective of the current application is to establish an experimental system to study effects of adipocyte-secreted PRL on breast cancer cells and adipocyte-breast cancer cells crosstalk and further establish the mechanisms by which PRL-activated PAK1 contributes to breast cancer. The central hypothesis is that that adipocyte-produced prolactin enhances invasiveness, tumorigenicity and metastatic potential of breast cancer cells through activation of PAK1 kinase and pTyr- PAK1 is a biomarker to predict metastatic potential of these breast cancer cells. The rational for the proposed research is that breast adipocytes secret adipocytokines including PRL, which may influence breast tumor behavior. PRL promotes JAK2 activation and tyrosyl phosphorylation of PAK1 in breast cancer cells. The central hypothesis will be tested by pursuing the following specific aims: Specific Aim 1 will test our working hypothesis that PAK1 activated by adipocyte-derived PRL enhances breast cancer cell invasiveness and cell motility via Tec kinase and that adipocyte-breast cancer cells crosstalk induces secretion of MMP-11 by adipocytes and MMP-1 by breast cancer cells. Specific Aim 2 will test our working hypothesis that PAK1 activated by adipocyte-derived PRL affects tumorigenicity and metastatic potential of breast cancer cells in vivo and that pTyr-PAK1 can serve as a biomarker to predict breast tumor metastasis. Under the sub-aim, characterized PAK1 phospho-specific antibodies will be used to evaluate metastatic potential of the cells at an early stage of BC. This proposal is conceptually innovative because it is expected to vertically advance and expand our understanding of how obesity through adipocyte-secreted PRL influences BC and the unique role of PRL-activated PAK1 in this process. This proposal is technically innovative as well because it will employ unique PAK1 phospho-specific antibodies. The proposed research is significant because the elucidation of PRL/PAK1 mediated intracellular signaling pathways will enhance our understanding of the mechanisms involved in regulation of BC and will lead to development of PAK1-based tools for BC diagnosis.

项目概要/摘要我们对脂肪细胞分泌的激素催乳素（PRL）如何与脂肪细胞分泌的了解存在差距。丝氨酸/苏氨酸 PAK1 连接协调调节人类乳腺癌 (BC) 的进展脂肪细胞-乳腺癌细胞串扰。本研究的长期目标是建立PAK1，由脂肪细胞分泌的PRL，作为BC细胞转移潜力的新诊断工具，并提供所需的深入了解底层机制。当前应用程序的总体目标是建立一个研究脂肪细胞分泌的PRL对乳腺癌细胞和脂肪细胞乳腺影响的实验系统癌细胞串扰并进一步建立 PRL 激活的 PAK1 促进的机制乳腺癌。中心假设是脂肪细胞产生的催乳素增强侵袭性，通过激活 PAK1 激酶和 pTyr- 实现乳腺癌细胞的致瘤性和转移潜力 PAK1 是预测这些乳腺癌细胞转移潜力的生物标志物。拟议的理由研究表明乳腺脂肪细胞分泌包括PRL在内的脂肪细胞因子，可能影响乳腺肿瘤行为。 PRL 促进乳腺癌细胞中 JAK2 激活和 PAK1 酪氨酰磷酸化。这将通过追求以下具体目标来检验中心假设：具体目标 1 将检验我们的工作假设脂肪细胞来源的 PRL 激活 PAK1 增强乳腺癌细胞的侵袭性和细胞通过 Tec 激酶进行运动，并且脂肪细胞-乳腺癌细胞串扰通过以下方式诱导 MMP-11 的分泌：乳腺癌细胞的脂肪细胞和 MMP-1。具体目标 2 将检验我们的工作假设：PAK1 脂肪细胞来源的PRL激活影响体内乳腺癌细胞的致瘤性和转移潜力 pTyr-PAK1可以作为预测乳腺肿瘤转移的生物标志物。在分目标下，特征化的 PAK1 磷酸化特异性抗体将用于评估细胞的转移潜力 BC 早期。该提案在概念上具有创新性，因为它有望纵向推进并扩大我们对肥胖如何通过脂肪细胞分泌的 PRL 影响 BC 及其独特作用的理解 PRL 激活的 PAK1 在此过程中的作用。该提案在技术上也具有创新性，因为它将采用独特的 PAK1 磷酸化特异性抗体。拟议的研究意义重大，因为阐明了 PRL/PAK1 介导的细胞内信号通路将增强我们对其机制的理解参与 BC 的监管，并将导致基于 PAK1 的 BC 诊断工具的开发。