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:10120306
- 负责人:
- 金额:$ 55.58万
- 依托单位:
- 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:
- 关键词:3-DimensionalAlveolarApicalApplications GrantsBiochemicalBiogenesisBreast Cancer CellBreast Epithelial CellsCa(2+)-Transporting ATPaseCalcineurinCalciumCell DeathCell PolarityCell SurvivalCell membraneCellsComplexCouplesDataDatabasesDevelopmentDrug TargetingERBB2 geneGrantHeat-Shock Proteins 90HumanHuman MilkIn VitroKnockout MiceKnowledgeLactationLesionLysosomesMalignant - descriptorMalignant NeoplasmsMammary glandMediatingMembraneMilkMouse Mammary Tumor VirusMultiprotein ComplexesMusNoninfiltrating Intraductal CarcinomaPMCA1 proteinPhosphorylationRegulationResistanceSTAT3 geneScaffolding ProteinSignal TransductionTestingTherapeuticTrastuzumabUp-RegulationWeaningapical membranebasolateral membranecancer cellexperimental studyezrinin vivoin vivo calcium imaginginsightknock-downmalignant breast neoplasmmortalitynoveloverexpressionresponsescaffoldtumor
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)顶膜。
哺乳。它负责运输60%-70%的牛奶钙。断奶后,乳汁淤积迅速减少。
PMCA2表达,导致细胞内钙离子持续增加。初步数据显示,这
细胞内钙的升高可能是乳汁停滞与激活的生化信号。
溶酶体生物发生、STAT3磷酸化和溶酶体依赖性细胞死亡(LDCD)。在上一个周期中
这笔资金,我们记录了PMCA2在乳腺癌中也重新表达,并与
ERBB2/HER2水平和死亡率增加。我们现在已经定义了PMCA2、NHERF1、
ErbB2及其下游生化产物膜滞留所需的Ezrin、HSP90和ErbB2
发信号。抑制PMCA2增加细胞内钙离子,并导致依赖于PKCA的细胞分解
这种多蛋白复合体以及ErbB2的泛素化、内化和降解。正常情况下
MECS、NHERF1、Ezrin和PMCA2在顶端质膜内相互作用,而ErbB2与
不同的支架蛋白称为Erbin,位于基底侧膜。初步数据显示,在DCIS中
在病变和浸润性乳腺癌细胞中,PMCA2、Ezrin和NHERF1与Erbin和ErbB2混合
这种复合体在曲妥珠单抗耐药的乳房中表达显著上调
癌细胞。这项资助申请的前提/假设有三个:1)乳汁淤积迅速减少
PMCA2的表达导致细胞内钙离子持续增加,进而触发LDCD;2)
细胞极性的丧失使顶端的PMCA2-NHERF1-Ezrin复合体与
基侧,Erbin-ErbB2复合体,促进ErbB2介导的转化;3)上调
PMCA2和ErbB2之间的相互作用有助于曲妥珠单抗耐药性的产生。我们
提出3个具体目标。目标1将研究细胞内钙离子增加的机制
浓度激活溶酶体生物发生、STAT3和LDCD。目标2将测试PMCA2的变化
ErbB2/HER2基因的定位促进恶性转化目标3将测试是否进一步上调
PMCA2、NHERF1、Ezrin、Erbin、HSP90和ErbB2之间的相互作用有助于曲妥珠单抗
抵抗。这些实验将为乳汁淤积的机制提供重要的新知识
触发内卷曲。他们将通过以下方式为MEC转型的早期步骤提供重要的见解
ERBB2。他们将验证针对ErbB2/HER2阳性肿瘤的新的癌细胞特异性药物靶点,并将测试
在曲妥珠单抗耐药癌症中破坏这些相互作用的潜在治疗价值。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John J Wysolmerski其他文献
John J Wysolmerski的其他文献
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{{ truncateString('John J Wysolmerski', 18)}}的其他基金
Heterodimerization of the Calcium-sensing receptor with the GabaB receptors in the breast.
乳房中钙敏感受体与 GabaB 受体的异二聚化。
- 批准号:
10457479 - 财政年份:2020
- 资助金额:
$ 55.58万 - 项目类别:
Heterodimerization of the Calcium-sensing receptor with the GabaB receptors in the breast.
乳房中钙敏感受体与 GabaB 受体的异二聚化。
- 批准号:
10674985 - 财政年份:2020
- 资助金额:
$ 55.58万 - 项目类别:
Heterodimerization of the Calcium-sensing receptor with the GabaB receptors in the breast.
乳房中钙敏感受体与 GabaB 受体的异二聚化。
- 批准号:
10249173 - 财政年份:2020
- 资助金额:
$ 55.58万 - 项目类别:
PMCA2 regulates mammary gland involution and breast cancer
PMCA2 调节乳腺退化和乳腺癌
- 批准号:
10674696 - 财政年份:2014
- 资助金额:
$ 55.58万 - 项目类别:
PMCA2 regulates mammary gland involution and breast cancer
PMCA2 调节乳腺退化和乳腺癌
- 批准号:
10441515 - 财政年份:2014
- 资助金额:
$ 55.58万 - 项目类别:
PMCA2 regulates mammary gland involution and breast cancer
PMCA2 调节乳腺退化和乳腺癌
- 批准号:
10267724 - 财政年份:2014
- 资助金额:
$ 55.58万 - 项目类别:
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