Jeong Jaekwang, VanHouten Joshua N, Dann Pamela, Kim Wonnam, Sullivan Catherine, Yu Herbert, Liotta Lance, Espina Virginia, Stern David F, Friedman Peter A, Wysolmerski John J
Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520;
Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):E282-90. doi: 10.1073/pnas.1516138113. Epub 2016 Jan 4.
In the lactating mammary gland, the plasma membrane calcium ATPase2 (PMCA2) transports milk calcium. Its expression is activated in breast cancers, where high tumor levels predict increased mortality. We find that PMCA2 expression correlates with HER2 levels in breast cancers and that PMCA2 interacts with HER2 in specific actin-rich membrane domains. Knocking down PMCA2 increases intracellular calcium, disrupts interactions between HER2 and HSP-90, inhibits HER2 signaling, and results in internalization and degradation of HER2. Manipulating PMCA2 levels regulates the growth of breast cancer cells, and knocking out PMCA2 inhibits the formation of tumors in mouse mammary tumor virus (MMTV)-Neu mice. These data reveal previously unappreciated molecular interactions regulating HER2 localization, membrane retention, and signaling, as well as the ability of HER2 to generate breast tumors, suggesting that interactions between PMCA2 and HER2 may represent therapeutic targets for breast cancer.
在哺乳期乳腺中，质膜钙ATP酶2（PMCA2）负责转运乳汁中的钙。其表达在乳腺癌中被激活，肿瘤中该蛋白水平高预示着死亡率增加。我们发现，PMCA2的表达与乳腺癌中的HER2水平相关，且PMCA2在富含肌动蛋白的特定膜结构域中与HER2相互作用。敲低PMCA2会增加细胞内钙水平，破坏HER2与热休克蛋白90（HSP-90）之间的相互作用，抑制HER2信号传导，并导致HER2的内化和降解。调控PMCA2水平可调节乳腺癌细胞的生长，敲除PMCA2可抑制小鼠乳腺肿瘤病毒（MMTV）-Neu小鼠体内肿瘤的形成。这些数据揭示了此前未被认识到的调节HER2定位、膜保留和信号传导的分子相互作用，以及HER2引发乳腺肿瘤的能力，表明PMCA2与HER2之间的相互作用可能是乳腺癌的治疗靶点。
