A recent study from the University of California, Santa Cruz, indicates that having a first pregnancy early in life may help protect against breast cancer by preventing certain age-related changes in breast cells. The research, published in Nature Communications, used a mouse model to simulate human aging and reproductive history.
Researchers found that as mammary tissue ages without pregnancy, it accumulates hybrid cells that express markers of both luminal and basal lineages. These “confused” cells also display an inflammatory signal known as IL-33. According to the study, IL-33 can promote uncontrolled cell growth—a step toward tumor formation. However, early pregnancy appears to prevent these hybrid cells from building up.
“By forcing the cells to choose a specific job and stick to it, pregnancy maintains the ‘lineage integrity’ of the tissue,” said Shaheen Sikandar, assistant professor of molecular, cell, and developmental biology at UC Santa Cruz and corresponding author of the study. “This suggests that the protective power of pregnancy comes from its ability to stop these hybrid cells from accumulating in the first place—the focus of our work now.”
The researchers examined mammary glands in aged mice that had either experienced an early pregnancy or had never been pregnant. Their findings are relevant because most breast cancer diagnoses occur after age 50 and most women have their first child between ages 20 and 33.
Using single-cell RNA sequencing technology, the team analyzed thousands of mammary epithelial cells. They discovered that exposure to IL-33 caused young mammary epithelial cells to behave like those from older animals who had not been pregnant. This included increased cell proliferation and organoid formation—changes linked with early tumor development—especially when combined with suppression of Trp53, a key tumor-suppressor gene.
“Taken together, the findings could help explain why the protective effect of pregnancy takes years to emerge, and why it persists into later life, by showing how early reproductive events can leave a lasting imprint on the aging breast,” said Andrew Olander, graduate student in Sikandar’s lab and lead author.
Pregnancy was also found to restore balance among different types of mammary cells in aged mice. In particular, it normalized expansion of basal cells seen with aging and reduced organoid-forming capacity across cell types. Additionally, luminal cells retained molecular signatures associated with post-pregnancy involution—a state which may enhance immune system recognition.
Although this research was conducted using mice rather than humans, scientists believe its principles likely apply more broadly due to similarities between species in breast tissue structure and cancer risk patterns. The study does not establish direct causation between hybrid cell accumulation and cancer but identifies these changes as possible contributors for future investigation.
“Our study lays the groundwork for understanding the complex relationship between aging and pregnancy in the mammary gland,” Sikandar said. “Future work will be focused on further understanding the role of the ‘confused’ hybrid cells in developing breast cancer.”
Other co-authors include Paloma Medina, Veronica Haro Acosta, Sara Kaushik, and Matijs Dijkgraaf—all affiliated with UC Santa Cruz’s Department of Molecular, Cell & Developmental Biology or related institutes such as Genomics Institute or Institute for Biology of Stem Cells. Funding came from sources including The Hellman Foundation and grants from NIH/National Cancer Institute.
