A first pregnancy early in life may significantly reduce a woman’s risk of developing breast cancer decades later by preventing harmful age-related changes in breast cells, according to new research from the University of California, Santa Cruz.
The study, published in Nature Communications, provides fresh insight into a long-standing mystery in breast cancer biology: why aging increases breast cancer risk, while early pregnancy offers long-term protection. Using a mouse model designed to closely mirror human aging and reproductive history, researchers found that pregnancy fundamentally alters how mammary tissue ages, limiting the buildup of abnormal cells that may later seed tumors.
“Our findings suggest that pregnancy acts as a kind of cellular reset,” said Shaheen Sikandar, an assistant professor of molecular, cell, and developmental biology at UC Santa Cruz and the study’s corresponding author. “It forces breast cells to commit to specific identities and maintain that identity over time, which appears to reduce cancer risk later in life.”
Solving a decades-old puzzle
Scientists have long observed that women who experience their first pregnancy before age 30 have a lower lifetime risk of breast cancer, even though pregnancy can briefly increase cancer risk in the years immediately following childbirth. Until now, however, the cellular mechanisms behind this long-term protective effect have remained unclear.
Rather than focusing on the short-term changes after pregnancy, the UC Santa Cruz team took a much longer view. They examined mammary tissue from aged mice—roughly equivalent to postmenopausal women—comparing animals that had experienced an early pregnancy with those that had never been pregnant.
This approach is especially relevant because roughly three-quarters of breast cancer diagnoses occur after age 50, while most women in the United States have their first child between their early 20s and early 30s.
Aging breast tissue and the rise of “confused” cells
Using single-cell RNA sequencing, the researchers analyzed thousands of individual mammary epithelial cells to understand how aging and pregnancy shape breast tissue over time. In aged mice that had never been pregnant, they identified a growing population of abnormal “hybrid” cells.
These cells are described as “confused” because they simultaneously express markers of two distinct mammary cell types—luminal and basal—rather than committing to one. Importantly, the cells also produce IL-33, an inflammatory signaling molecule associated with uncontrolled cell growth, a key early step in tumor development.
“Loss of cellular identity is a hallmark of many cancers,” the researchers noted, and prior studies suggest that breast tumors often arise from cells that gradually lose their normal roles as tissues age.
Crucially, the study found that early pregnancy largely prevents these hybrid cells from accumulating. In mice that had been pregnant, mammary tissue aged in a more orderly way, without the same buildup of potentially dangerous cells.
Testing the role of inflammatory signaling
To better understand the role of IL-33, the team exposed mammary epithelial cells from young mice to the molecule. The results were striking: the treated cells began to behave like those from aged, never-pregnant mice.
IL-33 exposure increased cell proliferation and encouraged the formation of organoids—miniature tissue-like structures—particularly when combined with suppression of Trp53, a well-known tumor-suppressor gene. These changes mirror early features of tumor development, strengthening the link between IL-33–producing hybrid cells and cancer risk.
Pregnancy restores balance in aging breast tissue
Beyond reducing the number of hybrid cells, pregnancy also corrected other age-related shifts in mammary tissue. In aged mice that had never been pregnant, basal cells expanded disproportionately as the animals aged. This imbalance was largely normalized in mice that had experienced an early pregnancy.
Both basal and luminal cells from aged, previously pregnant mice also showed a reduced ability to form organoids, suggesting lower growth potential overall. At the same time, luminal cells retained molecular signatures associated with post-pregnancy involution, a state that may make them more visible to the immune system.
The researchers speculate that this heightened immune surveillance could provide an additional layer of protection against cancer.
Long-term effects of early reproductive events
Andrew Olander, a graduate student in Sikandar’s lab and the study’s lead author, said the findings help explain why pregnancy’s protective effect takes years to emerge but lasts well into later life.
“Early reproductive events appear to leave a lasting imprint on how the breast ages,” Olander said. “That imprint may shape cancer risk decades down the line.”
Implications for breast cancer prevention
Although the research was conducted in mice, the authors argue that the findings are likely relevant to humans, given similarities in mammary gland biology and cancer patterns. The study does not prove that hybrid cells directly cause breast cancer, but it identifies them as a plausible contributor to age-related risk—and a potential target for future prevention strategies.
“Our work lays the foundation for understanding how aging and pregnancy interact at the cellular level in the breast,” Sikandar said. “The next step is to determine exactly how these ‘confused’ cells contribute to cancer development and whether they can be safely targeted.”
The study was co-authored by Paloma Medina, Veronica Haro Acosta, Sara Kaushik, and Matijs Dijkgraaf, all affiliated with UC Santa Cruz’s Department of Molecular, Cell, & Developmental Biology and related research institutes. Funding was provided by the Hellman Foundation, a National Institutes of Health/National Cancer Institute fellowship, and additional research grants to the team.
