Influence of Estrogen Treatment on and Cells in ER Breast Cancer: Insights from Single-Cell Analysis of Patient-Derived Xenograft Models.

A 100% ER positivity is not required for an endocrine therapy response. Furthermore, while estrogen typically promotes the progression of hormone-dependent breast cancer via the activation of estrogen receptor (ER)-α, estrogen-induced tumor suppression in ER breast cancer has been clinically observed. With the success in establishing estrogen-stimulated (SC31) and estrogen-suppressed (GS3) patient-derived xenograft (PDX) models, single-cell RNA sequencing analysis was performed to determine the impact of estrogen on and tumor cells. We found that 17β-estradiol (E2)-induced suppression of GS3 transpired through wild-type and unamplified ERα. E2 upregulated the expression of estrogen-dependent genes in both SC31 and GS3; however, E2 induced cell cycle advance in SC31, while it resulted in cell cycle arrest in GS3. Importantly, these gene expression changes occurred in both and cells within the same breast tumors, demonstrating for the first time a differential effect of estrogen on cells. E2 also upregulated a tumor-suppressor gene, , in GS3. The apoptosis gene set was upregulated and the G2M checkpoint gene set was downregulated in most cells after E2 treatment. In summary, estrogen affected pathologically defined ER tumors differently, influencing both and cells. Our results also suggest to be a potential marker of estrogen-suppressed tumors.