Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells

• DOI: 10.4161/cbt.5.6.2708
• Publication Date: 2010-07-13T21:17:44Z
• Authors: Phillip C.C. Liu; Xiangdong Liu; Yanlong Li; Maryanne Covington; Richard Wynn; Reid Huber; Milton Hillman; Gengjie Yang; Dawn Ellis; Cindy Marando; Kamna Katiyar; Jodi Bradley; Kenneth Abremski; Mark Stow; Mark Rupar; Jincong Zhuo; Yun-Long Li; Qiyan Lin; David Burns; Meizhong Xu; Colin Zhang; Ding-Quan Qian; Chunhong He; Vaqar Sharief; Lingkai Weng; Costas Agrios; Eric Shi; Brian Metcalf; Robert Newton; Steven Friedman; Wenqing Yao; Peggy A. Scherle; Gregory Hollis; Timothy C. Burn
• Keywords: Ectodomain; ADAM10

Overexpression and activating mutations of ErbB family members have been implicated in the development progression a variety tumor types. Cleavage HER2 receptor by an as yet unidentified ectodomain sheddase has shown to liberate extracellular domain (ECD) leaving fragment with constitutive kinase activity that can provide ligand-independent growth survival signals cell. This process is clinically relevant since ECD serum levels metastatic breast cancer patients are associated poorer prognosis. Thus, inhibition may novel therapeutic approach for cancer. We describe use transcriptional profiling, pharmacological vitro approaches identify major source activity. Real-time PCR was used those ADAM which were expressed shedding cell lines. siRNAs selectively inhibited ADAM10 expression reduced shedding. In addition, we profiled over 1000 small molecules panel MMP proteins; positive correlation observed only between reduction based assay. Finally, studies demonstrate combination low doses Herceptin, selective inhibitors decrease proliferation overexpressing lines while inhibitors, do not inhibit ADAM10, no impact. These results consistent being determinant shedding, which, treating cancers active signaling.