Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis

Abstract

The female mammary epithelium undergoes reorganization during development, pregnancy, and menopause, linking higher risk with breast cancer development. To characterize these periods of complex remodeling, here we report integrated 50 K mouse and 24 K human mammary epithelial cell atlases obtained by single-cell RNA sequencing, which covers most lifetime stages. Our results indicate a putative trajectory that originates from embryonic mammary stem cells which differentiates into three epithelial lineages (basal, luminal hormone-sensing, and luminal alveolar), presumably arising from unipotent progenitors in postnatal glands. The lineage-specific genes infer cells of origin of breast cancer using The Cancer Genome Atlas data and single-cell RNA sequencing of human breast cancer, as well as the association of gland reorganization to different breast cancer subtypes. This comprehensive mammary cell gene expression atlas (https://mouse-mammary-epithelium-integrated.cells.ucsc.edu) presents insights into the impact of the internal and external stimuli on the mammary epithelium at an advanced resolution.

Histone Variant H2A.J Is Enriched in Luminal Epithelial Gland Cells

“…Previously published human and mouse mammary gland single-cell RNA-seq data [23,24] were analyzed using a modified version of bioinformatic scripts made available by Saeki et al (DOI: 10.5281/zenodo.4674274). The modified code is available in Zenodo (DOI: 10.5281/zenodo.5517186).…”

“…We used previously published single-cell RNA-seq data to examine H2AFJ expression in mammary epithelial cells in female humans and mice [23,24]. 24,280 mammary epithelial cells from 4 healthy women aged 17-36 years old were grouped into 3 clusters by UMAP (uniform manifold approximation and projection): a basal-myoepithelial cluster (labeled B) and 2 luminal cell clusters (L1 and L2) (Figure 3A,B) [24].…”

Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts

“…ScRNA-seq analysis also provides fundamental insights into the regulatory activity of PBDEs on distinct populations in normal mammary glands in the presence of estrogen. Furthermore, we expanded our scRNA-seq analysis to study the effect of PBDEs on the differentiation of mammary epithelial cells by integrating human and mouse datasets from our and others' studies, thereby constructing a mammary cell gene expression atlas [137]. One group utilized scRNA-seq technology, although not directly related to cancer research, to investigate the transcriptomic changes induced by a known xenoestrogen, di (2-Ethylhexyl) phthalate (DEHP), exposure.…”

“…Menopause is a critical WOS because of its hypersensitivity to endocrine-disrupting chemicals due to the decline of endogenous estrogen [208]. Studies from our group have discovered that PBDEs, the flame retardants in household products, enhance E2-mediated regrowth of mammary glands, augment E2-facilitated gene expression, and modulate immune regulation, thus increasing the risk of developing breast cancer [136][137][138][139]. Importantly, like the WOS in female breast cancer, there appears to be a heightened sensitivity of the prostate to these exogenous estrogens during the critical developmental windows, such as in utero, the neonatal period and puberty.…”

“…By taking advantage of the PDX-breast cancer model and scRNA-seq analysis in surgically menopausal (ovariectomized/OVX) mouse models, our group has identified the response to exposure to the xenoestrogen PBDE by various types of cells within mammary tumors and normal breast tissue [125]. At the single-cell level, by integrating mouse and human datasets, we also describe the landscape of transcriptional changes in mammary glands upon endogenous and PBDE at different WOS in a woman's life [136,137,139].…”