Researchers have found that in healthy women, some breast cells that otherwise appear normal may contain chromosome abnormalities typically associated with invasive breast cancer, according to a recent study published by Lin et al in Nature. The findings challenged conventional thinking on the genetic origins of breast cancer, which could influence early cancer detection methods.
Background
Epithelial cells, which line and cover the inside and outside of the body, are the cells that are believed to give rise to cancer.
The study built on previous work on the Human Breast Cell Atlas, which profiled over 714,000 cells to generate a comprehensive genetic map of normal breast tissue at the cellular level.
Study Methods and Results
In the study, the researchers examined the breast tissue samples of 49 healthy women without known disease who were undergoing breast reduction surgery. They investigated chromosomal copy number changes in normal breast tissues compared with clinical breast cancer data. Using single-cell sequencing and spatial mapping, the researchers specifically investigated breast epithelial cells.
The researchers discovered that a median of 3.19% of the normal cells from breast tissue contained a gain or loss of chromosomes—a condition known as aneuploidy—and that over 82.67% of them had expanded copy number changes commonly found in invasive breast cancers. Notably, a woman’s age correlated significantly with the frequency of aneuploid cells and number of copy number changes, with older women accumulating more of these cellular changes.
The most frequent changes were additional copies of chromosome 1q and losses of chromosomes 10q, 16q, and 22q—commonly found in invasive breast cancers. Previous studies have identified specific genes in these regions that are also associated with breast cancer.
The data revealed that these aneuploid cells represented both of the known cell lineages of the mammary gland, which have distinct gene signatures that can either be positive or negative for estrogen receptors (ER). One lineage had copy number changes similar to ER-positive breast cancers, whereas the other appeared to have events consistent with ER-negative breast cancers, highlighting their potentially different origins.
Conclusions
The results of the study could question the current understanding of normal breast tissue. As earlier detection methods using molecular diagnostics along with ductal carcinoma in situ and biopsies continue to be developed, the researchers highlighted the potential risk of identifying false positives, since the cells can mistakenly be confused with invasive breast cancer.
“A cancer researcher or oncologist seeing the genomic picture of these normal breast tissue cells would classify them as invasive breast cancer,” stressed senior study author Nicholas Navin, PhD, Chair of Systems Biology at The University of Texas MD Anderson Cancer Center. “We’ve always been taught that normal cells have 23 pairs of chromosomes, but that appears to be inaccurate because every healthy woman that we analyzed in our study had irregularities, bringing up the very provocative question about when cancer actually occurs,” he suggested.
The researchers indicated that further longitudinal studies are needed to identify which potential risk factors, if any, may cause these cells to become cancerous. Additionally, epithelial cells are found in many body systems, highlighting the possibility that these findings can translate to other organs.
“It just shows that our bodies are imperfect in some ways, and we can generate these types of cells over our lifetime,” Dr. Navin underscored. “This has pretty big implications not just for the field of breast cancer, but potentially for multiple cancer types. This doesn’t necessarily mean that everyone is walking around with precancer, but we need to think about ways to set up larger studies to understand the implications for developing cancer,” he concluded.
Disclosure: The research in this study was supported by the National Cancer Institute, the Cancer Prevention and Research Institute of Texas Single Cell Genomics Center, the American Cancer Society, and the Rosalie B. Hite Fund for Cancer Research Fellowship. For full disclosures of the study authors, visit nature.com.
