As many people with a family history of cancer know all too well, inheriting a mutation in the BRCA1 or BRCA2 genes dramatically increases cancer risk. People with these mutations can be 75% more likely to develop breast cancer during their lifetime and also face a higher risk of ovarian and prostate cancer. In hopes of catching cancer early, people with BRCA mutations typically undergo extra mammograms and screening procedures and some even elect to have risk-reducing surgeries such as mastectomies.
With V Foundation funding, Karlene A. Cimprich, PhD, from Stanford Cancer Institute is making new discoveries about how BRCA mutations lead to cancer. Her work is revealing potential new therapeutic targets for BRCA-related tumors and laying the groundwork for a new blood test to catch cancer sooner.
“Individuals with BRCA mutations frequently get cancers earlier in life,” said Cimprich. “We want to understand what drives this process, including what the BRCA genes do normally that isn’t taking place when mutations are present, and how this leads to early development of cancer.”
Escaping the nucleus
It all began years ago when Cimprich and her colleagues discovered something odd that occasionally happens inside the cell nucleus, the place where cells extract information from DNA to make proteins that keep the cell running. Normally, cells make RNA in the nucleus and then shuttle it out to the cytoplasm to serve as a template for making proteins. However, Cimprich found that under certain conditions RNA gets tangled with DNA in the nucleus, creating a structure called an R-loop.
If the cell doesn’t catch and correct this mistake, it can damage the DNA. After Cimprich’s discovery, another research group found that the BRCA1 and BRCA2 genes help stop R-loops from forming. This suggests BRCA mutations could allow R-loops to accumulate, leading to DNA damage.
Studying cells that lack normal BRCA1 and BRCA genes, Cimprich and her colleagues made another surprising discovery: in these cells, R-loops were not only found in the nucleus but also in the cell’s cytoplasm. The researchers gave these errant sections of DNA and RNA floating around the cytoplasm a name that sounds like science fiction: “cytoplasmic hybrids.”
Understanding harmful hybrids
The V Foundation awarded the team funding to find out where cytoplasmic hybrids come from, why they form and how they affect cell function. In the process, the researchers developed new imaging tools and new methods for isolating and genetically sequencing the hybrids.
“These cytoplasmic hybrids have never been reported before,” Cimprich said. “We not only showed they exist but developed ways to observe and characterize them.”
The researchers found that cytoplasmic hybrids activate an immune response that eventually leads to cell death. “This was a surprising finding and means that it might be possible to develop therapies that help boost this immune response in patients with BRCA1 or BRCA2 mutations,” Cimprich said. “We’re now working to better understand this immune response and how cancer cells have figured out how to evade this cell death.”
The researchers are also working on developing a way to isolate these cytoplasmic hybrids in blood. This could make it possible to develop a blood test that would offer a less invasive, more cost-efficient way of screening for BRCA-linked cancer. Toward this goal, they are now beginning to analyze blood samples from volunteers to see how well they can detect the cytoplasmic hybrids in blood and whether their levels correlate with cancer progression and initiation. They suspect that levels of the hybrids increase as cancer starts to form.
Cimprich says that the V Foundation support was critical in helping her bring together a group of Stanford scientists from different fields, which inspired new ideas and approaches. For example, Jim Ford, a geneticist and medical oncologist, encouraged the group to look for the cytoplasmic hybrids in blood. Also, team member Aaron Straight’s expertise in imaging was instrumental in figuring out how to visualize the cytoplasmic hybrids.
She also credits the V Foundation for being willing to take on a project that was high risk because it was different and new. “Our results were not exactly what we expected, but what we found out was still very new and exciting,” Cimprich said. “These findings are now driving much of the new research in my lab.”