The Human Breast Cell Atlas: A New View of Breast Biology

Researchers who created the world's largest and most comprehensive atlas of normal breast tissue say it offers a unique way to understand breast biology and identify treatment targets for diseases such as breast cancer . The research adds a new dimension to efforts to unravel the body's complexity and provides crucial insights that may contribute to treating breast diseases, particularly breast cancer.

A Major Project

The human body contains approximately 200 different cell types, 12 of which occur in normal breast tissue. Previous breast tissue studies focused on epithelial cells, which can give rise to cancer. Nonepithelial cell types, however, had not been investigated in depth using genomic approaches. Spatial mapping techniques can map cells within tissues.

Senior researcher Nicholas Navin of MD Anderson Cancer Center in Texas says, “We are excited to have completed this major project,” adding: "By using several technologies, we could describe all the different cell types and states in the breast's main regions in great detail. We think this tool will be very useful to anyone studying breast cancer, other diseases such as mastitis, breast development or lactation failure."

On June 28, 2023, Nature published the findings of this notable project, part of the global Human Cell Atlas Consortium, which creates cellular reference maps for every organ system in the human body.

Study Methods and Findings

The researchers collected and examined 220 breast tissue samples from women undergoing breast reduction or mastectomy (breast removal). Of these women, 46% were White, 41% Black and 7% Hispanic, while 6% had unknown ethnicity.

To create the Human Breast Cell Atlas, they used samples from the 126 participating women to profile a total of 714 thousand cells using single-cell and spatial genomic methods.

Study Workflow Diagram: Overview and workflow of the Human Breast Tissue Atlas project: breast tissue samples collected from various sources, followed by single-cell and single-nucleus RNA sequencing (10x Genomics), and spatial analysis using CODEX (Akoya Biosciences), spatial transcriptomics (Visium 10x) Genomics) and smFISH (Resolve Biosciences and Vizgen Merscope). 

The researchers classified 12 major cell-type clusters in detail, including three types of epithelial cells, lymphatic cells, vascular cells, T cells, B cells, myeloid cells, adipocytes, mast cells, fibroblasts and perivascular cells.

Below is an illustration of adult human breast anatomy and a pathological H&E examination showing the main cell types in breast tissue. 

They also identified 58 biological cell states, including differences associated with ethnicity, age, body mass index (BMI), obesity, menopausal status, pregnancy and the number of births among healthy women.

Spatial mapping allowed researchers to examine samples' RNA and protein composition and understand where and how different cell types were located. The techniques resolved the composition of known cell types and new cell states across four main breast regions: milk-producing lobules, milk-carrying ducts, fibroblast-rich connective tissue and predominantly fatty adipose regions.

More Immune Cells Than Expected

Researchers expected few immune cells in normal tissue. Instead, they found that 16.7% of all normal breast tissue cells were immune cells, such as myeloid cells, natural killer T cells and B cells. These were found in three of the four main tissue regions, predominantly around ducts and lobules.

They also found an unexpectedly high proportion (7.4%) of perivascular cells, including pericytes and vascular smooth muscle cells.

Below are subtypes of the different cell types in human breast tissue (a dendrogram created using BioRender).

The researchers further identified substantial differences in breast tissue composition and cell states by ethnicity, age and menopausal status. For example, Black women are disproportionately affected by aggressive subtypes such as triple-negative breast cancer and inflammatory breast cancer, yet little is known about the reasons for these disparities.

They found substantial differences in breast tissue from women older than 50 compared with younger women, as well as differences in cell states by menopausal status. Obesity, BMI, pregnancy status and breast density showed smaller differences in cell types and states.

Conclusions

The researchers emphasize that more work may be needed to understand the functions of many cell states and explore other factors that could substantially advance knowledge of human breast biology and disease. For example, studying different immune cells could help develop more effective immunotherapies for some breast cancer subtypes and define the role of immune cells in breast cancer progression.

The Human Breast Cell Atlas project continues and is actively recruiting participants to improve and expand its datasets. The data are freely available and can be accessed at navinlabcode.github.io .