权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

PMCA2 regulates mammary gland involution and breast cancer

PMCA2 调节乳腺退化和乳腺癌

基本信息

批准号：
10267724
负责人：
John J Wysolmerski
金额：
$ 54.47万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-10 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10267724
关键词：
3-Dimensional Alveolar Apical Applications Grants Biochemical Biogenesis Breast Cancer Cell Breast Epithelial Cells Ca(2+)-Transporting ATPase Calcineurin Calcium Cell Death Cell Polarity Cell Survival Cell membrane Cells Complex Couples Data Databases Development Drug Targeting ERBB2 gene Grant Heat-Shock Proteins 90 Human Human Milk In Vitro Knockout Mice Knowledge Lactation Lesion Lysosomes Malignant - descriptor Mammary gland Mediating Membrane Milk Mouse Mammary Tumor Virus Multiprotein Complexes Mus Noninfiltrating Intraductal Carcinoma PMCA1 protein Phosphorylation Regulation Resistance STAT3 gene Scaffolding Protein Signal Transduction Testing Therapeutic Trastuzumab Up-Regulation Weaning apical membrane basolateral membrane cancer cell experimental study ezrin in vivo in vivo calcium imaging insight knock-down malignant breast neoplasm mammary mortality novel overexpression refractory cancer response scaffold tumor

项目摘要

PMCA2 is a calcium pump expressed in the apical membrane of mammary epithelial cells (MECs) during lactation. It is responsible for transporting 60-70% of milk calcium. After weaning, milk stasis rapidly decreases PMCA2 expression, causing a sustained increase in intracellular calcium. Preliminary data suggest that this rise in intracellular calcium may serve as the biochemical signal that couples milk stasis to activation of lysosome biogenesis, STAT3 phosphorylation and lysosome-dependent cell death (LDCD). In the last cycle of this grant, we documented that PMCA2 is also re-expressed in breast cancers and correlates with ErbB2/HER2 levels and increased mortality. We have now defined interactions between PMCA2, NHERF1, Ezrin, HSP90 and ErbB2 that are required for membrane retention of ErbB2 and its downstream biochemical signaling. Inhibition of PMCA2 increases intracellular calcium and causes a PKCa-dependent disassembly of this multiprotein complex as well as the ubiquitinylation, internalization and degradation of ErbB2. In normal MECs, NHERF1, ezrin and PMCA2 interact within the apical plasma membrane while ErbB2 interacts with a different scaffolding protein called Erbin, at the basolateral membrane. Preliminary data show that, in DCIS lesions and in invasive breast cancer cells, PMCA2, Ezrin and NHERF1 intermix with Erbin and ErbB2 throughout the plasma membrane and that this complex is greatly upregulated in trastuzumab-resistant breast cancer cells. The premise/hypothesis of this grant application is three-fold: 1) that milk stasis rapidly decreases PMCA2 expression causing sustained increases in intracellular calcium, which, in turn, trigger LDCD; 2) that loss of cell polarity enables novel interactions between the apical, PMCA2-NHERF1-Ezrin complex and the basolateral, Erbin-ErbB2 complex that accelerate ErbB2-mediated transformation; and 3) that upregulation of interactions between PMCA2 and ErbB2 contribute to the development of trastuzumab resistance. We propose 3 specific aims. Aim 1 will examine the mechanisms whereby increased intracellular calcium concentrations activate lysosome biogenesis, STAT3 and LDCD. Aim 2 will test whether alterations in PMCA2 localization accelerate malignant transformation by ErbB2/HER2. Aim 3 will test whether further upregulation of interactions between PMCA2, NHERF1, Ezrin, Erbin, HSP90 and ErbB2 contributes to trastuzumab resistance. These experiments will provide important new knowledge of the mechanisms by which milk stasis triggers involution. They will contribute important insight into the early steps of transformation of MECs by ErbB2. They will validate novel cancer cell-specific drug targets for ErbB2/HER2-positive tumors and will test the potential therapeutic value of disrupting these interactions in trastuzumab-resistant cancers.

PMCA2是一种钙泵，表达于乳腺上皮细胞（MECs）的顶膜