UC Santa Cruz study finds link between pregnancy and reduced breast cancer risk

SANTA CRUZ — A recent UC Santa Cruz study, published in Nature Communications scientific journal, uncovered clues in a decadeslong mystery surrounding the relationship between early pregnancy and breast cancer risk.

Early pregnancy, between the ages of 20 and 30, has been shown to reduce the risk of breast cancer later in life. The reason why has stumped scientists for years. Now, a research group from UC Santa Cruz has found evidence suggesting that early pregnancy can permanently change the way breast cells age, preventing the accumulation of a type of cells that may contribute to tumor growth.

Shaheen Sikandar, an assistant professor of molecular, cell and developmental biology at UC Santa Cruz, noticed a gap in breast cancer research. Though many studies had looked at aging and breast cancer risk, most of those studies were done on mice that had never been pregnant.

“That really shocked me when I started,” said Andrew Olander, a graduate student in Sikandar’s lab and the lead author of the study. “This is a huge variable, but it’s really important … a large part of our population has undergone pregnancies.”

Shortly after Sikandar set up her lab at UCSC in late 2020, she began planning for a study that would address this gap. The idea caught Olander’s attention as soon as he joined the lab — his mother had recently retired from her career as an obstetrician and gynecologist, and he thought it would be fitting for him to carry on contributing to women’s health.

The research team did its initial study with two groups of mice. One group underwent pregnancies between 3-6 months of age — the equivalent of around 20 to 30 years old in humans. The other group of mice never had pregnancies. Then, the research team left the mice alone for several months, letting them age naturally.

When the mice were between 18 and 24 months old, which is similar to 56 to 69 years old in humans, the team analyzed all of the mammary cells from both groups of mice using a technique called single-cell RNA sequencing. After this analysis, the team was left with a map showing all of the cell types that were present in the aged mouse mammary glands.

Looking at the map, Olander and Sikandar saw the main two types of mammary cells — basal cells, which provide structural support, and luminal cells, which produce milk. But, unexpectedly, there was also a third population of cells in the mice that had never been pregnant. At first, the researchers thought the cells might not be real; that maybe the map was showing some kind of artifact from the sequencing technology. To find out for sure, Olander decided to treat some more aged mammary cells with antibodies that would allow him to identify if these mysterious hybrid cells were, in fact, present.

To the researchers’ surprise, Olander found the hybrid cells in his experiment. This was intriguing to Sikandar because in other body systems, cells that lose their identities or become hybrids of different cell types sometimes begin to grow quickly, and can contribute to tumor formation. If that was true of the hybrid cells she and Olander had just discovered, it could explain why women who don’t become pregnant earlier in life have a higher risk of breast cancer later in life.

To learn more about the hybrid cells, the research team studied them in vitro, including within organoid models. These organoids are three-dimensional structures that mimic living tissue, allowing scientists to understand how cell types work in normal circumstances.

The scientists found that the hybrid cells produced a signaling molecule called Interleukin 33. In normal cells, the molecule acts as an alarm, alerting the immune system when tissue is injured. There was no apparent reason that the molecule should be produced in aging breast tissue cells, which are usually quite inactive. To understand more about what the molecule could be doing, the research team treated healthy mammary cells and young mice with Interleukin 33. The young mammary cells began to behave more like aged cells, and began to grow and divide much more.

“We were kind of surprised,” Sikandar said. “We didn’t expect such a strong phenotype.”

The study has left Sikandar, Olander and the rest of the lab with several questions, which they are eager to explore. Their study suggests that pregnancy permanently changes the way mammary cells age, potentially preventing the development of hybrid cells. If the hybrid cells do, in fact, contribute to breast cancer, this could explain why early pregnancy can reduce the likelihood of breast cancer later in life.

Carman Man-Chung Li, a professor of cancer biology at the University of Pennsylvania, found the study out of Sikandar’s lab intriguing. The evidence that these cells express the signaling molecule Interleukin 33, and that the molecule could have an impact on tumor formation, is significant, Li said.

“This exciting finding opens the door to future research on the mechanisms underlying this cancer risk and new therapeutic approaches,” Li wrote in an email to the Sentinel.

Now, Sikandar and Olander are working to answer two crucial questions: Do the hybrid cells lead to cancer formation? And is there a way to stop those cells from accumulating in the first place?

Sikandar said her lab has recently received funding to do more experiments and try to answer those questions. Eventually, the research could lead to some kind of preventative therapy that would stop the formation of hybrid cells and possibly reduce the risk of breast cancer. That’s exciting to Sikandar because prevention is one of the most important areas of focus for breast cancer treatment, alongside better treatments for late-stage metastatic disease.

“One in 8 women will be diagnosed with breast cancer in their lifetime,” Sikandar said. “(Reducing) that 1 in 8 number to 1 in 16, even that would be amazing.”