A new study from cell biologists at the University of California, Santa Cruz, provides fresh insight into why having a first pregnancy early in life is linked to a lower risk of breast cancer decades later. The research suggests that early pregnancy protects against age-related cellular changes in breast tissue that are associated with tumor development, effectively reshaping how mammary cells age over time.
Published in Nature Communications, the study tackles a long-standing question in breast cancer research: why aging increases breast cancer risk, while early pregnancy confers lasting protection. Until now, the cellular mechanisms behind this protective effect have remained unclear.
Using a mouse model designed to closely mimic human aging and reproductive history, the researchers found that pregnancy fundamentally alters the trajectory of mammary tissue aging. In mice that never experienced pregnancy, aging breast tissue accumulated abnormal “hybrid” cells—cells that simultaneously exhibit characteristics of two distinct mammary cell types. These confused cells were marked by inflammatory signaling that can promote unchecked growth, an early step toward cancer.
In contrast, mice that experienced pregnancy early in life showed a striking reduction in these abnormal cells later in life. Pregnancy appeared to act as a long-term “reset,” preventing the buildup of cells that could seed tumors years down the line.
“Pregnancy forces cells to commit to a specific identity and maintain it,” said Shaheen Sikandar, assistant professor of molecular, cell, and developmental biology at UC Santa Cruz and corresponding author of the study. “By preserving this lineage integrity, pregnancy prevents the accumulation of hybrid cells that may contribute to cancer risk as tissue ages.”
Modeling decades of breast cancer risk
Breast cancer risk rises steadily with age, with roughly three-quarters of diagnoses occurring after age 50. At the same time, women who have their first child before age 30 experience a lower lifetime risk of developing the disease. To explore this paradox, the researchers took a longer view than most previous studies, which have typically focused on the short-term changes that occur immediately after pregnancy.
Instead, the team examined mammary tissue in aged mice at a stage roughly equivalent to postmenopausal age in humans. They compared animals that had never been pregnant with those that underwent an early pregnancy—mirroring women who have a first child between their 20s and early 30s and are assessed after age 50.
Using single-cell RNA sequencing, the researchers analyzed thousands of individual mammary epithelial cells, allowing them to map how pregnancy and aging together reshape cell populations and gene activity over time.
A risky cell population emerges with age
One of the study’s most notable findings was the accumulation of hybrid cells in aging mammary tissue that had never experienced pregnancy. These cells expressed markers of both luminal and basal mammary lineages and were located in the basal layer, a region often implicated in the origins of breast tumors.
The hybrid cells also produced high levels of IL-33, an inflammatory signaling molecule known to stimulate cell proliferation. When researchers exposed mammary epithelial cells from young mice to IL-33, the cells began to resemble those found in aged, never-pregnant animals—showing increased growth and tumor-like behavior.
These effects were amplified when IL-33 signaling was combined with suppression of Trp53, a major tumor-suppressor gene. Under these conditions, cells readily formed organoids, or miniature tissue structures, a hallmark of early cancer-related changes.
“Together, these results help explain why the protective effects of pregnancy take years to become apparent and why they persist later in life,” said Andrew Olander, a graduate student in the Sikandar Lab and lead author of the study. “Early reproductive events leave a lasting imprint on how the breast ages.”
Pregnancy restores balance in aging breast tissue
Beyond reducing the number of hybrid cells, pregnancy also corrected broader age-related imbalances in mammary tissue. In aged mice that had been pregnant, the abnormal expansion of basal cells typically seen with aging was normalized. Both basal and luminal cells also showed a reduced capacity for excessive growth.
In addition, luminal cells in previously pregnant mice retained molecular signatures linked to post-pregnancy involution—a tissue remodeling phase that may enhance immune surveillance. The researchers suggest this could further lower cancer risk by making abnormal cells more visible to the immune system.
Implications for breast cancer prevention
Although the findings are based on mouse models, the researchers believe the underlying biology is likely relevant to humans, given similarities in mammary gland structure and breast cancer epidemiology. While the study does not directly prove that hybrid cells cause cancer, it identifies them as a compelling contributor to age-related risk and a possible target for future prevention strategies.
“Our work lays the foundation for understanding how pregnancy and aging interact in the mammary gland,” Sikandar said. “The next step is to determine exactly how these hybrid cells contribute to breast cancer development and whether they can be targeted therapeutically.”
The study was conducted by researchers in UC Santa Cruz’s Department of Molecular, Cell, and Developmental Biology, with contributions from Paloma Medina, Veronica Haro Acosta, Sara Kaushik, and Matijs Dijkgraaf, along with affiliations to the Genomics Institute, Department of Biomolecular Engineering, and the Institute for the Biology of Stem Cells.
