Researchers have discovered and mapped the signaling network between two previously unconnected proteins, exposing a link that, if broken, could cut off cancer cell growth at its starting point.
A team led by scientists at The University of Texas MD Anderson Cancer Center reported the tie between epidermal growth factor receptor (EGFR), a well-known cancer drug target, and MCM7, a protein vital to the first step in DNA replication, in the June issue of Cancer Cell.
"MCM7 overexpression marks cell proliferation and is associated with glioblastoma and colorectal, ovarian and esophageal cancers, among others. Yet the mechanisms that regulate its function have been unclear," said co-lead author Tzu-Hsuan Huang, Ph.D., formerly of MD Anderson's Department of Molecular and Cellular Biology and now with Amgen, Inc., in Boston.
MCM7 is important to DNA licensing, Huang said, "which is the very first step in DNA replication and, in effect, gives the DNA replication machinery permission to proceed." Its function had not previously been tied to EGFR signaling, which leads to DNA synthesis and cell growth, and is often dysfunctional in human cancers.
EGFR tells Lyn to tell MCM7 to fuel cancer growth
In a series of experiments, Huang, co-lead author Longfei Huo, Ph.D. a research scientist in Molecular and Cellular Biology, and colleagues tracked the signaling cascade from EGFR activation to activation of another signaling molecule called Lyn to MCM7 ignition.
Both EGFR and Lyn are tyrosine kinases, which activate other proteins by attaching phosphate groups to them. The team found that activated EGFR phosphorylates Lyn, which in turn tags MCM7 with phosphate groups. They found all three actions are correlated in human lung and breast cancer tumors.
Mice with high expression of either Lyn or MCM7 had breast cancer tumor volumes two to three times greater than those with low expression.
Pathway shortens patient survival
"We established that this signaling pathway correlates with EGFR status and poor survival in breast cancer patients," said study senior author Mien-Chie Hung, Ph.D., chair and professor of the department and holder of the Ruth Legett Jones Distinguished Chair.