Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 193, Issue 1, Pages 84-102Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2022.09.007
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Genetically engineered mouse models with overexpression of Esr1 and CYP19A1 revealed divergent disease processes in mammary glands due to distinct molecular pathophysiological intrusions into estrogen signaling during reproductive senescence. Esr1 overexpression led to higher rates of preneoplasia and cancer compared to CYP19A1 overexpression. Tamoxifen and letrozole exposure down-regulated cell proliferation genes and resolved differences between the two models.
Molecular-level analyses of breast carcinogenesis benefit from vivo disease models. Estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) overexpression targeted to mammary epithelial cells in genetically engineered mouse models induces largely similar rates of pro-liferative mammary disease in prereproductive senescent mice. Herein, with natural reproductive senes-cence, Esr1 overexpression compared with CYP19A1 overexpression resulted in significantly higher rates of preneoplasia and cancer. Before reproductive senescence, Esr1, but not CYP19A1, overexpressing mice are tamoxifen resistant. However, during reproductive senescence, Esr1 mice exhibited responsiveness. Both Esr1 and CYP19A1 are responsive to letrozole before and after reproductive senescence. Gene Set Enrichment Analyses of RNA-sequencing data sets showed that higher disease rates in Esr1 mice were accompanied by significantly higher expression of cell proliferation genes, including members of prog-nostic platforms for women with early-stage hormone receptor-positive disease. Tamoxifen and letrozole exposure induced down-regulation of these genes and resolved differences between the two models. Both Esr1 and CYP19A1 overexpression induced abnormal developmental patterns of pregnancy-like gene expression. This resolved with progression through reproductive senescence in CYP19A1 mice, but was more persistent in Esr1 mice, resolving only with tamoxifen and letrozole exposure. In summary, genetically engineered mouse models of Esr1 and CYP19A1 overexpression revealed a diversion of disease processes resulting from the two distinct molecular pathophysiological mammary gland-targeted in-trusions into estrogen signaling during reproductive senescence. (Am J Pathol 2023, 193: 84-102; https://doi.org/10.1016/j.ajpath.2022.09.007)
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