A recent study from the University of California, Santa Cruz, indicates that an early first pregnancy may help protect against breast cancer later in life by preventing age-related changes in breast cells that are associated with tumor formation. The research, published in Nature Communications, used a mouse model to examine how pregnancy affects the aging process of mammary tissue.
Researchers found that as breast tissue ages without pregnancy, it accumulates abnormal “hybrid” cells. These cells attempt to function as two different types at once and display an inflammatory signal called IL-33. This molecule can trigger uncontrolled cell growth, which is an early step toward tumor development. However, the study showed that pregnancy acts as a “cellular reset button,” stopping these hybrid cells from accumulating.
“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 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 used single-cell RNA sequencing to analyze thousands of mammary epithelial cells in aged mice. They compared those who had experienced early pregnancies with those who had not. Their model reflects human reproductive patterns: most women in the United States have their first child between ages 20 and 33, while about 75% of breast cancer diagnoses occur after age 50.
One key finding was that hybrid cells expressing both luminal and basal markers accumulate with age unless interrupted by pregnancy. These cells are located in areas where tumors often originate when normal cell identity is lost over time.
To test whether IL-33 could drive harmful changes directly, scientists treated young mouse mammary epithelial cells with IL-33. The treatment caused these young cells to behave like those from older animals that had never been pregnant—showing increased proliferation and forming more organoids when combined with suppression of Trp53, a gene important for tumor suppression.
“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 also helped restore balance within mammary tissue beyond just reducing hybrid cell numbers. In mice who had been pregnant (parous), there was less expansion of basal cells—a change typically seen with aging—and both basal and luminal populations were less able to form organoids linked to tumor risk. Additionally, luminal cells retained signatures making them potentially more recognizable by immune defenses.
Although conducted in mice, researchers believe these biological mechanisms likely apply to humans due to similarities between species’ mammary gland structures and cancer trends. The presence of hybrid cells does not prove they cause cancer but points toward them as contributors to age-related risk—and possible targets for future prevention efforts.
“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 contributors include Paloma Medina, Veronica Haro Acosta, Sara Kaushik, and Matijs Dijkgraaf from UC Santa Cruz’s Department of Molecular, Cell & Developmental Biology; some are affiliated with additional campus institutes such as Genomics Institute and Institute for Biology of Stem Cells. Funding came from sources including the Hellman Foundation and grants from National Institutes of Health/National Cancer Institute.
