Dr. Li Ma, PhD, an assistant professor at The University of Texas MD Anderson Cancer Center, is figuring out ways to battle breast cancer by studying breast cancer cell resistance to radiation. Her group of researchers recently discovered that the protein called zinc finger E-box binding homeobox 1 (ZEB1) may allow breast cancer cells to persist despite radiation treatment.
“Radiation therapy causes cell death by inducing DNA ‘breaks,'” began Dr. Ma in a news release. “The rationale for treating tumors with radiation without damaging normal tissues is that, compared with normal cells, tumor cells are actively dividing and often have defects in DNA damage repair machinery.”
Yet, as explained in Nature Cell Biology, ZEB1 enhances cancer cells’ DNA damage response, effectively helping cancer cells repair the damage caused by radiation. ZEB1 acts as a “panic button” cancer cells can press in order to generate cancer stem cells and resist treatment.
“The cancer stem cells have been shown to promote radioresistance through activation of the DNA damage response system,” said Dr. Ma. “Our studies have shown that ZEB1 can induce a process known as epithelial-mesenchymal transition (EMT) which allows certain tumor to acquire cancer stem cell properties including radioresistance.”
To study the role of EMT in radioresistance, Ma’s team overexpressed the transcription factors Snail, Twist, or ZEB1 in non-transformed human mammary epithelial cells. Overexpression induced EMT, evidenced by morphology changes, and led to the cells’ survival upon radiation exposure. In trying to reverse EMT, the team further silenced the transcription factors and found that only ZEB1 knockdown reduced radioresistance.
Further delving into the mechanism, Dr. Ma’s team found the kinase known as ATM stabilizes ZEB1 in response to DNA damage, allowing it to interact with the enzyme USP7 and stabilize CHK1. This promotes homologous recombination-dependent DNA repair.
“Radiation therapy plays a key role in breast cancer management,” said Dr. Ma. “To overcome the obstacle of radioresistant tumor cells, it is important to identify the critical causes and to develop safe and effective new methods for treatment including the possible use of agents that target ZEB1 and which inhibit CHK1.”
Collaborators of Dr. Ma included MD Anderson’s Departments of Molecular and Cellular Oncology, Radiation Oncology, and Bioinformatics and Computational Biology. Other participating institutions included the University of Louisville Health Sciences Center, the Houston Methodist Research Institute, China Medical University, Taiwan, and The University of Texas Health Science Center Graduate School of Biomedical Sciences.
Funding was provided by the National Institutes of Health (R00CA138572, R01CA166051, R01CA181029 and U54CA151668) and a Cancer Prevention Research Institute of Texas scholar award (R1004).