A study conducted by cell biologists at the University of California, Santa Cruz, has found that an early first pregnancy may protect against breast cancer later in life by altering the way breast cells age. The research, published in Nature Communications, used a mouse model to simulate human aging and reproductive history.
Researchers compared mammary tissue from older mice that had experienced pregnancy with those that had not. They observed that aging breast tissue without prior pregnancy accumulates abnormal hybrid cells capable of switching identities, which is associated with tumor formation. These hybrid cells display an inflammatory signal known as IL-33.
IL-33 can lead to uncontrolled cell growth, a preliminary stage of tumor development. The study found that pregnancy functions as a "cellular reset button" preventing the buildup of these hybrid cells.
"A woman's risk of developing breast cancer rises steadily with age, with most diagnoses occurring after age 50. Meanwhile, having a first child before age 30 lowers lifetime risk," the researchers noted. To explore this connection, they studied mammary glands at an age comparable to postmenopausal women who had their first child between ages 20 and 30.
The team utilized single-cell RNA sequencing to analyze thousands of mammary epithelial cells and track changes due to aging and pregnancy. One significant finding was the presence of hybrid cells expressing markers from both major mammary lineages—luminal and basal—in aged mice without previous pregnancies. The location of these cells in the basal layer suggests potential importance for cancer risk since many tumors arise from cells losing their identity over time.
Further experiments showed that treating young mouse mammary epithelial cells with IL-33 made them behave like those from aged, never-pregnant animals. This exposure increased cell proliferation and organoid formation—characteristics linked to 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 the Sikandar Lab and lead author.
Pregnancy also corrected broader age-related imbalances in mammary tissue: aged parous mice did not show the usual expansion of basal cells seen with aging; both basal and luminal cell types showed reduced ability to form organoids. Luminal cells in these mice retained molecular features associated with "post-pregnancy involution," possibly making them more visible to immune surveillance—a factor suggested by authors as potentially lowering cancer risk further.
Although this work was conducted using mice, researchers believe these biological mechanisms are likely relevant for humans due to similarities in mammary gland structure and patterns seen in epidemiological studies. The study does not claim direct causation between hybrid cells and cancer but highlights them as plausible contributors to age-related risk and possible targets for prevention strategies.
"Our study lays the groundwork for understanding the complex relationship between aging and pregnancy in the mammary gland," said Sikandar. "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 as well as affiliates from other campus institutes. Funding came from sources including the Hellman Foundation and grants from National Institutes of Health/National Cancer Institute.
