Characterization of estrogen, progesterone and the endocrine-disrupting chemical-induced mouse mammary gland reorganization via single-cell RNA-sequencing

The mammary epithlium goes through the drastic reorganization during development, pregnancy, and menopause as well as by external hormones and its mimicry, which risks the gland for the specific type of breast cancer. Using a surgical menopausal (ovariectomized) mouse model, we assessed how mammary gland tissue was affected by 17ß-estradiol (E2), progesterone (P4) and polybrominated diphenyl ethers (PBDEs). Then, we integrated the transcriptomes of 50K mouse and 24K human mammary epithelial cells from five different datasets and four individuals obtained by single-cell RNA sequencing (scRNAseq). The results indicated a putative trajectory originating from the embryonic mammary stem cells and differentiating into the three different epithelial lineage (Basal, Luminal alveolar, and Luminal hormone sensing) that were presumably sustained by unipotent progenitors in the postnatal glands. The identified lineage-specific gene sets inferred cells of origin of breast cancer using The Cancer Genome Atlas data and scRNAseq of human breast cancer. The comprehensive mammary cell atlas presented novel insights into the impact of the internal and external stimulati on the mammary epithelium in an unprecedented resolution. Overall design: Female BALB/cj mice were ovariectomized 20 weeks before treatment. They were treated with 5 different conditions for 1 week; 1)Vehicle, 2) E2, 3) E2 and PBDEs, 4) E2 and P4, and 5) E2, P4 and PBDEs, . The 4th mammary glands were harvested and single-cell RNA sequencing was performed.