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：
10674696
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/10674696
关键词：
3-Dimensional Acceleration 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 Cytoplasm Data Databases Development Drug Targeting ERBB2 gene Grant Heat-Shock Proteins 90 Human 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 sodium-hydrogen exchanger regulatory factor 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 是在乳腺上皮细胞 (MEC) 顶膜中表达的钙泵哺乳期。它负责运输60-70%的乳钙。断奶后，奶淤迅速减少 PMCA2表达，导致细胞内钙持续增加。初步数据表明，这细胞内钙的升高可能作为将乳汁停滞与乳汁激活结合起来的生化信号。溶酶体生物发生、STAT3 磷酸化和溶酶体依赖性细胞死亡 (LDCD)。在最后一个周期中在这笔资助中，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 及其下游生化物质的膜保留所需的 Ezrin、HSP90 和 ErbB2 发信号。抑制 PMCA2 会增加细胞内钙并导致 PKCa 依赖性分解这种多蛋白复合物以及 ErbB2 的泛素化、内化和降解。正常情况下 MEC、NHERF1、ezrin 和 PMCA2 在顶端质膜内相互作用，而 ErbB2 与基底外侧膜上有一种不同的支架蛋白，称为 Erbin。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 混合整个质膜，并且该复合物在曲妥珠单抗耐药的乳腺中大大上调癌细胞。本次拨款申请的前提/假设有三个方面：1) 乳汁淤滞迅速减少 PMCA2 表达导致细胞内钙持续增加，进而引发 LDCD； 2）那个细胞极性的丧失使得顶端、PMCA2-NHERF1-Ezrin 复合物和基底外侧的 Erbin-ErbB2 复合物加速 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发展。我们提出3个具体目标。目标 1 将检查细胞内钙增加的机制浓度激活溶酶体生物合成、STAT3 和 LDCD。目标 2 将测试 PMCA2 是否发生改变 ErbB2/HER2 的定位加速恶性转化。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反抗。这些实验将为乳汁停滞的机制提供重要的新知识引发内卷化。他们将为 MEC 转型的早期步骤提供重要见解 ErbB2。他们将验证针对 ErbB2/HER2 阳性肿瘤的新型癌细胞特异性药物靶点，并将测试破坏曲妥珠单抗耐药癌症中这些相互作用的潜在治疗价值。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Calcium Metabolism and Breast Cancer: Echoes of Lactation?

钙代谢和乳腺癌：哺乳期的影响？

DOI：
发表时间：
2020-12
期刊：
影响因子：
0
作者：
Grinman, Diego;Athonvarungkul, Diana;Wysolmerski, John;Jeong, Jaekwang
通讯作者：
Jeong, Jaekwang

A Case of Hypercalcemia from PTHrP-Producing Fibromyxoid Sarcoma Responsive to Glucocorticoid Therapy.

对糖皮质激素治疗有反应的产生 PTHrP 的纤维粘液样肉瘤引起的高钙血症一例。

DOI：
发表时间：
2023-08
期刊：
影响因子：
4.2
作者：
Niu, Isabella;Hsiao, Edward C;Wustrack, Rosanna;Wysolmerski, John J;Dann, Pamela;Masharani, Umesh
通讯作者：
Masharani, Umesh

Intracellular calcium links milk stasis to lysosome-dependent cell death during early mammary gland involution.

细胞内钙将乳汁停滞与早期乳腺退化过程中溶酶体依赖性细胞死亡联系起来。

DOI：
发表时间：
2024-01-12
期刊：
影响因子：
0
作者：
Jeong, Jaekwang;Lee, Jongwon;Talaia, Gabriel;Kim, Wonnam;Song, Junho;Hong, Juhyeon;Yoo, Kwangmin;Gonzalez, David G;Athonvarangkul, Diana;Shin, Jaehun;Dann, Pamela;Haberman, Ann M;Kim, Lark Kyun;Ferguson, Shawn M;Choi, Jungmin;Wysolmerski, J
通讯作者：
Wysolmerski, J

The butyrophilin 1a1 knockout mouse revisited: Ablation of Btn1a1 leads to concurrent cell death and renewal in the mammary epithelium during lactation.

重新审视嗜丁蛋白 1a1 敲除小鼠：Btn1a1 的消除会导致哺乳期间乳腺上皮细胞同时死亡和更新。

DOI：
发表时间：
2021-12
期刊：
影响因子：
2.7
作者：
Jeong, Jaekwang;Kadegowda, Anil K G;Meyer, Thomas J;Jenkins, Lisa M;Dinan, Jerry C;Wysolmerski, John J;Weigert, Roberto;Mather, Ian H
通讯作者：
Mather, Ian H

HER2 signaling regulates HER2 localization and membrane retention.

HER2 信号传导调节 HER2 定位和膜保留。