Researchers reveal impact of genetic ancestry on breast cancer risk and cell diversity

By Pooja Toshniwal PahariaReviewed by Benedette Cuffari, M.Sc.Aug 20 2024

In a recent study published in Nature Medicine, researchers map the diverse cell types present in healthy breast tissue to elucidate the role of genetic ancestry in breast cancer risk.

Study: Single-nucleus chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry. Image Credit: Motortion Films / Shutterstock.com

The role of genetic ancestry in breast cancer

Various factors contribute to disparities in breast cancer outcomes, some of which include socioeconomic status, healthcare access, as well as genetic ancestry. Recent research suggests that genetic ancestry can affect the structure of the genome and patterns of genetic mutations in cancer. This may include variations in the types and frequencies of genetic mutations observed in cancer among individuals of different genetic ancestries, as well as chromatin accessibility during cancer development.

The researchers of the current study previously described 23 different epithelial states present in breast tissue biopsies obtained from health donors. Despite these advances, it remains unclear how genetic ancestry affects the state or condition of breast tissue cells and, subsequently, their influence on cancerous processes.

About the study

The Komen Tissue Bank was utilized to evaluate breast tissue samples obtained from 92 women with heterogeneous genetic origins. Deoxyribonucleic acid (DNA) was also isolated from donor blood for genetic ancestry mapping.

Spatial transcriptomics allowed the researchers to investigate gene expression variations between ductal and lobular epithelial cells. Epithelial cell gene expression characteristics were combined with spatial transcriptomics data to identify gene expression differences present in both cell types and integrate these differences with chromatin accessibility data.

Single-nucleus assays were also used in conjunction with transposase-access chromatin with single-nucleus ribonucleic acid sequencing (snRNA-seq) information from different ancestries, including African and European individuals. Both snRNA-seq and single-nucleus chromatin accessibility (snATAC)-seq data were integrated to identify cell types and states across genetic ancestries.

Integrin α6 (CD49f) and epithelial cellular adhesion molecule (EpCAM) expression levels were used to classify epithelial cell types as basal, luminal progenitor, and mature luminal. Differentially expressed genes (DEGs) were also identified among all cell types and analyzed in the context of genetic ancestry.

Computational tools like SCENIC were used to infer gene regulatory networks, whereas Signaic was used for DNA motif analysis to identify transcription factor binding site motifs enriched in specific cell types.

The role of regulatory mechanisms in healthy breasts was also determined using a chromatin accessibility map and gene expression data that concentrated on estrogen receptor 1 (ESR1), forkhead box A1 (FOXA1), and GATA binding protein 3 (GATA3) for luminal hormone-sensing (LHS) cells.

ESR1 gene chromatin accessibility in LHS, luminal adaptive secretory precursor (LASP), and basal-myoepithelial (BM) cells was also determined by comparing gene expression in Indigenous American-enriched clusters to clusters 1, 12, and 18 in LASP cells.

Study findings

A total of ten distinct cell types were identified in breast tissue samples, some of which included epithelial cells, endothelial cells, adipocytes, fibroblasts, T-cells, and macrophages. Significant overlap was observed between genes enriched in various cell types, with certain markers enriched in three epithelial subtypes based on chromatin accessibility, gene expression, and transcriptional regulons.

Of the 71 genetic regulatory networks, 66 were significantly different among the three subtypes of epithelial cells. Motifs for transcription factor (TF) binding were more abundant among chromatin-accessible areas in each cell type.

Estrogen receptor (ER) binding sites were identified in chromatin-accessible areas of LASP and LHS cells but fewer sites among BM cells. This observation is significant, as the presence of ER binding sites in these cells may suggest their role as cells of origin in estrogen receptor-positive (ER+) breast cancer.  

Specific markers were found to be compatible chromatin accessibility, gene expression, and transcriptional regulons that distinguish BM, LHS, and LASP breast epithelial cells. LHS cell gene signatures are abundant in luminal A, luminal B, and human epidermal growth factor receptor 2 (HER2+) breast cancer subtypes, thus indicating that LHS cells are responsible for about 80% of breast cancers.

Metabolic pathways were more abundant in ductal cells, whereas mitogen-activated protein kinase (MAPK) pathways were more abundant in lobular epithelial cells. This observation suggests biological distinctions present between normal epithelial cells in breast ducts and lobules.

Significant genetic variations were observed among alveolar progenitor cells from Indigenous American individuals and stromal fibroblasts among African women. Indigenous American breast tissue samples exhibited higher ESR1 levels, which may affect estrogen signaling in their breast tissues and, as a result their increased susceptibility to ER+ breast cancers as compared to women of other ancestries.

Comparatively, the breast tissues of African women exhibited a more abundant fibroblast subtype, which can significantly influence the tumor microenvironment by promoting the secretion of growth factors, cytokines, and extracellular matrix components that may contribute to cancer invasion and metastasis.

The discovery of this potentially tumor-promoting microenvironment may clarify why African women are at a greater risk of developing more aggressive forms of breast cancer, such as triple-negative breast cancer (TNBC).

Implications

The study findings provide important insights into the role of genetic ancestry in health breast tissue biology and how these variabilities in cell type and biomarker expression can impact the risk of breast cancer in certain patient populations.

These biological differences in the breast tissue across women of different ancestries emphasizes the importance of personalized medicine that addresses the specific needs of women from diverse racial backgrounds to ultimately improve patient outcomes.