Researchers have created the world’s largest and most comprehensive atlas of normal breast tissue—the Human Breast Cell Atlas—which may provide an unprecedented understanding of mammary biology and help identify therapeutic targets for diseases such as breast cancer, according to a recent study published by Kumar et al in Nature.
Background
The human body contains roughly 200 different cell types, 12 of which are found in normal breast tissue. Previous studies on breast tissue have focused primarily on epithelial cells—given that these have been known to give rise to cancer—but nonepithelial cell types have not been studied in depth using genomic approaches. Spatial mapping techniques are capable of creating a map of the cells within the tissue environment.
“We are thrilled to see the completion of this monumental 7-year project,” explained senior study author Nicholas Navin, PhD, Professor and Chair of Systems Biology, Director of the Cancer Prevention and Research Institute of Texas Single Cell Genomics Center, and Co-Director of the Advanced Technology Genomics Core at The University of Texas MD Anderson Cancer Center. “We were able to leverage many technologies to define, in a very granular way, all the different cell types and cell states in each of the main areas of the breast. We expect this tool will be highly useful for anyone studying breast cancer and other diseases such as mastitis, as well as breast development and lactation failure,” he said.
The new project is part of the global Human Cell Atlas consortium, which is generating cellular reference maps for every organ system in the human body.
Study Methods and Results
In the new study, the researchers collected and examined 220 breast tissue samples from women undergoing breast reduction or mastectomy surgery. Among these women, 46% of them were White, 41% were Black, 7% were Hispanic, and 6% were of unknown ethnicity.
To create the Human Breast Cell Atlas, they used single-cell and spatial genomic methods to profile more than 714,331 cells from 126 of the women who participated in the study. The researchers performed a highly detailed classification of 12 major cell type clusters—including 3 types of epithelial cells, lymphatic cells, vascular cells, T cells, B cells, myeloid cells, adipocytes, mast cells, fibroblasts, and perivascular cells. The wide-ranging dataset also identified 58 biological cell states as well as differences based on the ethnicity, age, body mass index (BMI), obesity, menopause status, pregnancy, and number of births of healthy women.
The spatial mapping techniques allowed researchers to look at the RNA and protein composition of the samples to understand how and where the different cell types resided. These techniques resolved the composition of known cell types and new cell states in the four main regions currently known in the breast: the lobular milk-producing areas, ductal areas that transport milk, connective tissue composed of fibroblasts, and adipose areas made up of primarily fatty tissue.
The researchers anticipated that few immune cells would be found in normal tissue. However, they discovered that 16.7% of all cells in normal breast tissue were composed of immune cells such as myeloid cells, natural killer T cells, and B cells. Additionally, these immune cells were located primarily around ducts and lobules in three of the four major tissue regions.
The researchers also found an unexpectedly high proportion (7.4%) of perivascular cells—including pericytes and vascular smooth muscle cells.
Further, the researchers revealed significant differences in breast tissue composition and cell states that were dependent upon ethnicity, age, and menopause status. For example, Black women are disproportionately affected by aggressive breast cancer subtypes such as triple-negative breast cancer and inflammatory breast cancer, yet little is known about the underlying causes of these disparities.
The researchers also discovered significant differences in the breast tissue of women aged over 50 years compared with younger women, as well as differences in cell states dependent on menopause status. Obesity, BMI, pregnancy status, and breast density also showed some smaller differences in the changes of cell types and cell states.
Conclusions
The researchers emphasized that more studies may be needed to further understand the functional role of many of these cell states and to focus on other factors that may significantly advance the knowledge of human breast biology and disease. For instance, exploring the nuances of different immune cells could help researchers develop more effective immunotherapies for some subtypes of breast cancer and define the role of immune cells in breast cancer progression, and understanding the differences seen in baseline cell states in breast tissues from Black women and White women could highlight potential markers for cancer risk prediction.
The researchers noted that the Human Breast Cell Atlas project is ongoing and is actively recruiting participants to build upon and improve the data sets. The data are freely available and can be accessed at navinlabcode.github.io.
Disclosure: The research in this study was supported by the Chan Zuckerberg Initiative, the National Cancer Institute, the Cancer Prevention and Research Institute of Texas Single Cell Genomics Center, the American Cancer Society, the Rosalie B. Hite Fund for Cancer Research Fellowship, and the California Institute for Regenerative Medicine Training Grant. For full disclosures of the study authors, visit nature.com.
