A new study from the University of California, Santa Cruz, suggests that having a first pregnancy early in life could protect against breast cancer decades later by preventing age-related changes in breast cells linked to tumor formation. Using a mouse model designed to mimic human reproductive history and aging, researchers discovered that pregnancy fundamentally alters the way mammary tissue ages, reducing the accumulation of abnormal cells that could later develop into cancer.
Published in Nature Communications, the study sheds light on a long-standing question in breast cancer research: while aging increases the risk of breast cancer, early pregnancy offers lasting protection. Until now, the cellular mechanisms behind this protective effect remained unclear.
Pregnancy Acts as a “Cellular Reset”
The researchers used single-cell RNA sequencing to compare the breast tissue of aged mice that had experienced pregnancy with those that had not. They found that, without pregnancy, aging mammary tissue accumulates a population of “hybrid” cells—cells exhibiting traits of two different mammary cell types simultaneously. These hybrid cells also produce IL-33, an inflammatory molecule that can trigger uncontrolled cell growth, a key step in tumor formation.
“Pregnancy acts as a cellular reset button,” said Shaheen Sikandar, assistant professor of molecular, cell, and developmental biology and corresponding author of the study. “It forces cells to commit to a specific role, preventing the buildup of these hybrid cells and maintaining the tissue’s lineage integrity.”
Modeling Decades of Risk
Most breast cancers are diagnosed after age 50, and studies show that women who have a first child before age 30 experience a lower lifetime risk. To model this in mice, researchers examined mammary glands at an age roughly equivalent to postmenopause in humans, comparing mice that had been pregnant early in life with those that had never been pregnant.
Using single-cell analysis, the team tracked thousands of individual mammary epithelial cells, revealing how pregnancy reshapes aging tissue at the cellular and molecular levels.
Age-Related “Hybrid” Cells Pose Risk
The study highlighted a unique population of hybrid cells, found in the basal layer of the mammary gland. These cells exhibit markers of both luminal and basal lineages and resemble cells that can lose their identity over time—a hallmark of potential tumor formation. Experiments treating young mammary cells with IL-33 caused them to behave like hybrid cells in aged, never-pregnant tissue, increasing proliferation and organoid formation, particularly when combined with suppression of Trp53, a key tumor-suppressor gene.
“These findings help explain why the protective effect of early pregnancy takes years to emerge and persists into later life,” said Andrew Olander, graduate student in the Sikandar Lab and lead author of the study.
Pregnancy Restores Cellular Balance
Beyond reducing hybrid cells, pregnancy corrected broader age-related imbalances in mammary tissue. In aged mice that had experienced pregnancy, the expansion of basal cells seen with aging was normalized, and both basal and luminal cells showed a reduced ability to form organoids. Luminal cells retained molecular signatures of “post-pregnancy involution,” which may enhance immune system surveillance and further reduce cancer risk.
Implications for Human Breast Cancer
Although conducted in mice, researchers believe the findings have relevance for humans, given similarities in mammary gland structure and cancer epidemiology. While the study does not prove hybrid cells directly cause cancer, it identifies them as a plausible contributor to age-related risk and a potential target for future prevention strategies.
“Our study provides new insights into how early reproductive events leave lasting imprints on the aging breast,” Sikandar said. “Future work will focus on understanding the role of these hybrid cells in breast cancer development.”
The study was conducted by Sikandar and colleagues Paloma Medina, Veronica Haro Acosta, Sara Kaushik, and Matijs Dijkgraaf at UC Santa Cruz. Funding came from the Hellman Foundation, a National Institutes of Health/National Cancer Institute fellowship, and a grant to Sikandar.
