The epidermal growth factor receptor (EGFR) often goes haywire in cancer, sending constant, urgent signals into a cell, telling it to grow and divide. But in oxygen-starved conditions, EGFR also stifles production of tumor-suppressing microRNAs, a team of scientists led by MD Anderson researchers reported online at the journal Nature.
"When hypoxia stresses a cell, signaling by EGFR prevents immature miRNAs from growing up to fight cancer," said senior author Mien-Chie Hung, Ph.D., professor and chair of MD Anderson's Department of Molecular and Cellular Oncology and holder of the Ruth Legett Jones Distinguished Chair.
While most cancer cells die when drugs are administered under oxygen-starved conditions, those that survive are highly resistant to subsequent treatment.
Hung said most of the miRNAs left stuck in adolescence by EGFR under hypoxia have previously been reported to have tumor-suppressing characteristics.
EGFR stifling of AGO2 associated with shorter patient survival
Hung and colleagues found that EGFR attaches phosphate groups to the protein argonaute 2 (AGO2), a crucial component of a three-protein complex that converts precursors into mature miRNAs capable of regulating gene expression. This phosphorylation keeps AGO2 from connecting properly with other proteins to form that miRNA-maturation machinery.
The scientists established the EGFR-AGO2 effect in cell line experiments, confirmed it in a mouse model and human breast cancer samples, then found that it reduced breast cancer patient survival.
The hypoxia-EGFR-AGO2 connection was strong in tumor samples from 128 breast cancer patients, but it was low or absent in normal breast tissue.
In 125 breast cancer cases analyzed by the team, half of 62 patients with high levels of phosphorylated AGO2 survived to 48 months and beyond. Median survival had not been reached for the 63 patients in the low-level group, but 78 percent had survived to 48 months.
A first: growth factor signaling regulates miRNA
The group's findings point to a potential new prognostic marker for breast cancer, Hung noted, but also provide the first evidence of a growth factor signaling pathway regulating miRNA maturation.
The two process have been separate, as if one "spoke Chinese and the other English," Hung said. "This is the first paper to show how they communicate." It's likely, Hung said, that other growth factors such as platelet-derived growth factor or insulin-like growth factor might also regulate miRNA processing.
Interestingly, this EGFR signaling occurs right up to the brink of the receptor's destruction by cellular processes triggered by oxygen-starved conditions. EGFR is pulled from its position sticking out of the cell's outer membrane and dragged into cavities called vesicles, from which it is shifted to membrane-bound lysosomes that dissolve proteins.
EGFR is known to continue signaling from the vesicles, so its capture prolongs its activity in hypoxic conditions.
MD Anderson news release