A recent study from the University of California, Santa Cruz, published in Nature Communications, sheds new light on a decades-old question: why early pregnancy reduces the risk of breast cancer later in life.
Previous research has shown that women who experience pregnancy between the ages of 20 and 30 face a lower likelihood of developing breast cancer, but the biological mechanisms behind this protective effect remained unclear. UC Santa Cruz researchers now suggest that early pregnancy can permanently alter the way mammary cells age, preventing the accumulation of certain hybrid cells that may contribute to tumor formation.
Shaheen Sikandar, an assistant professor of molecular, cell, and developmental biology at UC Santa Cruz, noted that most previous studies on breast aging were conducted in mice that had never been pregnant—a significant oversight given the role pregnancy plays in women’s health. “That really shocked me when I started,” said Andrew Olander, a Ph.D. student in Sikandar’s lab and the study’s lead author. “This is a huge variable, but it’s really important… a large part of our population has undergone pregnancies.”
The team conducted experiments on two groups of mice: one that experienced pregnancy between three and six months of age, roughly equivalent to 20–30 years in humans, and another that remained nulliparous. After allowing the mice to age naturally, researchers analyzed mammary cells from both groups using single-cell RNA sequencing, producing a detailed map of cell types in aged mammary tissue.
While basal cells, which provide structural support, and luminal cells, which produce milk, were expected, the team discovered a third, unexpected population in the mice that had never been pregnant. Initially suspected as a sequencing artifact, further tests confirmed the presence of these “hybrid cells.”
Sikandar explained that hybrid cells in other body systems often lose their identity, grow rapidly, and contribute to tumor formation. This raised the possibility that hybrid cells in mammary tissue could be linked to the higher breast cancer risk observed in women who do not become pregnant early in life.
Further investigation revealed that these hybrid cells produced Interleukin 33, a signaling molecule typically involved in alerting the immune system to tissue injury. Experiments showed that treating young mammary cells and mice with Interleukin 33 caused the cells to behave like aged cells, increasing growth and division—a surprising and potentially significant finding.
“Our study suggests that pregnancy may permanently change how mammary cells age, potentially preventing the development of hybrid cells,” Sikandar said. “If these hybrid cells contribute to breast cancer, this could explain why early pregnancy offers protective effects.”
Carman Man-Chung Li, a professor of cancer biology at the University of Pennsylvania, called the findings “exciting” and noted the potential for future research into new therapeutic approaches.
Sikandar and Olander are now focusing on two critical questions: whether hybrid cells directly lead to cancer, and whether it is possible to prevent their accumulation. The lab recently received funding to pursue these experiments, with the long-term goal of developing preventative therapies that could reduce breast cancer risk.
“One in eight women will be diagnosed with breast cancer in their lifetime,” Sikandar said. “Reducing that to one in sixteen, even, would be amazing.”
