Statins are commonly prescribed to lower cholesterol, but a recent study suggest certain types of breast cancer may respond to treatment with statins. Led by Carol Prives of New York’s Columbia University, the international team found when they treated breast cancer cells carrying a mutant p53 gene with statins, they stopped growing in the disorganized manner characteristic of tumors, and in some cases even died. However a lot more work needs to be done before the lab results translate into clinical success.
The team writes about their findings in a report published online in the journal Cell on 20 January.
In a statement to the press, Prives said they can’t make any definite conclusions until they know more, but:
“The data raises the possibility that we might identify subsets of patients whose tumors may respond to statins.”
“There are great implications, but nothing clinical yet. Perhaps one could do a clinical trial, and that may support these findings, or it may be more complicated,” she added.
p53 is a tumor suppressor gene. It helps control many aspects of cell growth, such as keeping it organized and stopping uncontrolled growth, which is characteristic of tumors.
Over 50% of us have a mutated form of p53. Many of these mutations don’t just disrupt the gene’s normal job, they also give it the ability to encourage, instead of hold back, the development of cancer.
Experiments in mice have shown that when they lack p53 they develop cancer and die. But when they carry mutant forms of p53 taken from tumors, they develop a more aggressive cancer.
However, what the mutant forms of p53 are actually doing is still not clear and poses a big question for cancer researchers, so Prives and colleagues decided to investigate it further.
First they studied cancer cells growing in an artificial system that replicates the three-dimensional structure of the human breast. There they found that cells with mutant p53 grew in a disorganized and invasive manner, just like breast cancer does in the human body.
But when they lowered the amount of cells carrying mutant p53 (so that a higher proportion carried the “normal” version of the gene), the cells grew more normally in their 3D structure.
The next stage was led by first author William Freed-Pastor, also of Columbia University. He and his colleagues found a pathway known as the mevalonate pathway was behind the structural changes in the disorganized growth of the cells carrying mutated p53.
This pathway is the same one that cholesterol-lowering statins target because it also makes cholesterol.
So the logical next step was to see what happens if you treat the cells with statins. When they did this, the researchers found the mutant p53 cells stopped their disorganized, invasive growth, and some of them even died.
They double-checked their results by adding back in some of the intermediates of the pathway that the statins destroy (like putting back the “stepping stones”) and showed this erased the effects of the drugs. It was important to do this to show that it wasn’t some other off-target effect of the drugs that was working.
Lastly, with co-authors from the University of Oslo in Norway, Freed-Pastor and Prives examined breast cancer tissue taken from tumors in human patients and found that mutations in p53 and a higher rate of activity in the mevalonate, cholesterol-building, pathway tend to coincide in humans as well:
“… p53 mutation correlates with highly expressed sterol biosynthesis genes in human breast tumors,” they write.
They conclude that:
“These findings implicate the mevalonate pathway as a therapeutic target for tumors bearing mutations in p53.”
However, while the findings are encouraging and may have clinical relevance, Prives emphasizes that a lot more work needs to be done to confirm that.
Written by Catharine Paddock PhD