Presence of normal p53, a tumor suppressor gene, instead of a mutated version, makes breast cancer chemotherapy with doxorubicin less effective. The preclinical study led by MD Anderson scientists was published today in the journal Cancer Cell.
The research, which challenges the existing paradigm, is another step closer to personalized cancer medicine for breast cancer.
"It's really important to understand the genetic defects a tumor cell has before we treat it," said lead author Guillermina Lozano, Ph.D., professor and chair of the Department of Genetics. "What we learned here is the complete opposite of what we expected. We thought tumors would respond better to treatment if the p53 gene were normal. But the opposite was true, and for a really interesting reason."
Lozano said the research in mouse models showed that non-mutated p53 halted cell division, initiating a senescence (cell aging) process that allowed cells to survive. These senescent cells produce factors that stimulate adjacent cells to grow, fueling the relapse. Mutant p53 cells do not arrest and proceed through the cell cycle into cell division with broken chromosomes caused by the chemotherapy.
"That's a signal for the cell to die," she said. "It can't go any farther."
P53 status crucial to predicting response
The tumor suppressor p53 is mutated or inactivated in the majority of cancers, and about one-third of breast cancers have mutations in the gene. It has long been thought that normal p53 results in a better chemotherapy response, but the evidence in breast cancer has been conflicting.
According to the National Cancer Institute, about 227,000 women in the United States are diagnosed with breast cancer each year.
In this study, doxorubicin-treated p53 mutant tumor cells did not stop cell proliferation, leading to abnormal mitoses and cell death, whereas tumors with normal p53 arrested, avoiding mitotic catastrophe.
"There are a lot of data out there on responses of women to doxorubicin and other drugs that break DNA," Lozano said. "The response rates were mixed, and we never understood the difference. Now we understand that we need to know the p53 status to predict a response."
Results consistent in mouse, human models
The scientists first examined the response to doxorubicin in mice with mammary tumors and the role of p53 in the chemotherapy process. When they analyzed the results, they found the mice that responded poorly to treatment had normal p53 genes, while the mice that responded best had mutated p53 genes.
Using human breast tumor cell lines with normal p53, the researchers then replicated the mouse experiment with the same results. When the cells were treated with doxorubicin, which is known commercially as Adriamycin®, they basically stopped. When the p53 gene was removed, the cells continued through the cell cycle and eventual destruction.
Future research to examine relapse
Lozano said the next piece of the research puzzle involves looking at what happens after breast cancer has been treated successfully but comes back.
"A lot of breast cancer tumors relapse," she said. "We want to find out what additional changes these cells acquire that allow them to bypass the cell death mechanism."
In addition to Lozano, the team included MD Anderson researchers James Jackson, Ph.D., Vinod Pant, Ph.D., Leslie Chang, Daniel Garza and Peirong Yang M.S., Department of Genetics; Qin Li M.S., Department of Genetics and The University of Texas Graduate School of Biomedical Sciences Program in Genes and Development, Houston; Alfonso Quintas-Cardama, M.D., and Taghi Manshouri, Ph.D., Department of Leukemia; Omid Tavana, Ph.D. Department of Immunology; Adel El-Naggar, MD., Ph.D., Department of Pathology; and Yi Li, Ph.D., Lester and Sue Smith Breast Center and Department of Molecular and Cell Biology, Baylor College of Medicine, Houston.
This project was funded by grants from the National Cancer Institute and the National Institutes of Health, a Theodore N. Law Endowment for Scientific Achievement and a Dodie P. Hawn Fellowship in Cancer Genetics Research.
About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 41 comprehensive cancer centers designated by the National Cancer Institute. For eight of the past 10 years, including 2011, MD Anderson has ranked No. 1 in cancer care in the "Best Hospitals" survey published annually in U.S. News & World Report.
Scott Merville | EurekAlert!
Scientists enlist engineered protein to battle the MERS virus
22.05.2017 | University of Toronto
Insight into enzyme's 3-D structure could cut biofuel costs
19.05.2017 | DOE/Los Alamos National Laboratory
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.
In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...
Dental plaque and the viscous brown slime in drainpipes are two familiar examples of bacterial biofilms. Removing such bacterial depositions from surfaces is...
For the first time, scientists have succeeded in studying the strength of hydrogen bonds in a single molecule using an atomic force microscope. Researchers from the University of Basel’s Swiss Nanoscience Institute network have reported the results in the journal Science Advances.
Hydrogen is the most common element in the universe and is an integral part of almost all organic compounds. Molecules and sections of macromolecules are...
22.05.2017 | Event News
17.05.2017 | Event News
16.05.2017 | Event News
22.05.2017 | Materials Sciences
22.05.2017 | Life Sciences
22.05.2017 | Physics and Astronomy