September 10, 2014
Protein ZEB1 promotes radioresistance in breast tumors
BY Ron Gilmore
Twist, Snail, Slug. They may sound like words in a children’s nursery rhyme, but they are actually the exotic names given to proteins that can generate cells with stem cell-like properties that have the ability to form diverse types of tissue.
One protein with the even more out-there name of ZEB1 (zinc finger E-box binding homeobox 1), is now thought to keep breast cancer cells from being successfully treated with radiation therapy, according to an MD Anderson study.
Li Ma, Ph.D., an assistant professor of Experimental Radiation Oncology, reported in this month’s issue of Nature Cell Biology that ZEB1 may actually be helping breast tumor cells repair DNA damage caused by radiation treatment by ramping up a first-line of defense known as DNA damage response pathway.
“Radiation therapy causes cell death by inducing ‘breaks’ in the DNA that lives inside the cells,” says Ma. Because much of their energy is spent rapidly dividing, tumor cells are less able than normal cells to repair DNA damage. But not always. When confronted with radiation, some tumor cells are able to “turn on” a DNA damage response. Until now, the question has always been: “How?”
The answer, Ma says, is ZEB1.
“Our studies have shown that ZEB1 can induce a process known as epithelial-mesenchymal transition, or EMT, which bestows certain tumors with cancer stem cell properties, including radioresistance.”
EMT is one way the body responds to wound healing and it is believed that cancer has found a method for using EMT to promote tumor growth.
ZEB1 achieves this unfortunate result through a complex chain of events that permit a gene known as ATM to stabilize the protein Chk1 that plays an important role in DNA damage response. ZEB1 promotes Chk1’s ability to allow tumor radioresistance through deployment of an enzyme called USP7.
The hope is that new methods for preventing radiation resistance may be developed by better understanding how this signaling pathway keeps tumor cells growing, despite being bombarded with toxic radiation treatments.