A study conducted by researchers at the University of California, Santa Cruz, has found that an early first pregnancy may help protect against breast cancer later in life by preventing certain age-related changes in breast cells. The research, published in Nature Communications, used a mouse model to explore how pregnancy affects the aging process of mammary tissue and its connection to tumor formation.
Scientists have long observed that while the risk of breast cancer increases with age, women who have their first child before age 30 tend to have a lower lifetime risk. The cellular reasons behind this protective effect have not been fully understood.
In this study, researchers compared the breast tissue of older mice that had experienced pregnancy with those that had not. They discovered that aging mammary tissue without prior pregnancy accumulates “confused” hybrid cells—cells showing characteristics of two different cell types and displaying an inflammatory marker called IL-33. This marker is associated with uncontrolled cell growth, which can be an early step toward tumor development.
The study found that pregnancy acts as a “cellular reset button,” preventing 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 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.”
To understand why most breast cancer diagnoses occur after age 50 but early pregnancies offer lasting protection, researchers examined mammary glands at a stage comparable to postmenopausal age in humans. Their model reflected women who had their first child between ages 20 and 30 and were studied after age 50—a period when about three-quarters of all breast cancer cases are diagnosed according to population data.
Using single-cell RNA sequencing technology, they analyzed thousands of individual mammary epithelial cells to observe how aging and reproductive history influence cell populations and gene activity over time.
One key finding was that these hybrid cells accumulate with age unless interrupted by pregnancy. These cells express markers for both luminal and basal lineages—two major types found in mammary glands—and are located where many studies suggest tumors often originate as normal identity is lost during aging.
The team also tested whether IL-33 itself could drive harmful changes by treating young mouse mammary epithelial cells with IL-33. The treated cells began behaving like those from aged animals without prior pregnancies: they proliferated more rapidly and formed organoids more readily, especially when combined with suppression of Trp53—a gene important for suppressing tumors.
“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, lead author and graduate student in Sikandar’s lab.
Pregnancy was also shown to correct other imbalances caused by aging in mammary tissue. In older mice that had been pregnant (parous), expansion typically seen among basal cells during aging was normalized; both basal and luminal cell types showed reduced capacity for forming organoids compared to never-pregnant controls. Additionally, luminal cells retained molecular features linked with post-pregnancy involution—a state possibly making them easier targets for immune surveillance.
Although conducted using mice rather than humans, researchers believe these biological principles likely apply across species due to similarities in gland structure and cancer patterns. While direct causation between hybrid cell accumulation and cancer has not been proven here, identifying these cells offers potential avenues for future prevention strategies.
“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, Matijs Dijkgraaf—all affiliated with UC Santa Cruz’s Department of Molecular, Cell & Developmental Biology or related institutes. Funding came from sources such as the Hellman Foundation and grants from NIH/National Cancer Institute.
