June 11, 2012
Intact tumor suppressor hinders one type of breast cancer chemotherapy
BY Scott Merville
A gene most commonly known as a tumor-suppressor appears to help breast cancer cells survive treatment by a common chemotherapy drug.
In the June 12 edition of Cancer Cell, MD Anderson researchers report that normal p53 thwarts the effects of doxorubicin while mutated versions of the gene improved the drug's effect. Doxorubicin is an anthracycline, a class of antibiotics used to treat a variety of cancers.
The p53 gene regulates the cell cycle. It's capable of stopping division when flaws in the cell are detected, summoning repair proteins to deal with DNA damage, or ordering the cell to kill itself (apoptosis) if the defects are beyond repair.
"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 MD Anderson's 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."
Normal p53 halted cell division after detecting DNA damage done by the drug. This inability to divide, called senescence, allowed the cells to survive.
These cells, Lozano and colleagues found, produce cell-signaling molecules called cytokines that stimulate adjacent cancer cells to grow, leading to relapse.
Mutant p53 cells do not arrest. Instead, they 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."
Mice with normal p53 treated with doxorubicin had less tumor shrinkage, quicker relapse and no sign of cancer cell death. Those with mutated p53 had greater tumor regression and p53-independent cell death. The same effect was observed in human tumor cell lines. 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.
"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."
Lozano's findings provide an explanation for how intact p53 might help tumor cells resist doxorubicin. The research team is focusing on additional factors that lead to breast cancer relapse.
This research was funded by grants from the National Cancer Institute of the National Institutes of Health.
Cancer Cell paper
MD Anderson news release