Overexpression of Estrogen Receptor a in Mammary Glands of Aging Mice Is Associated with a Proliferative Risk Signature and Generation of Estrogen Receptor a-Positive Mammary Adenocarcinomas

Age is a risk factor for human estrogen receptor-positive breast cancer, with highest prevalence following menopause. While transcriptome risk profiling is available for human breast cancers, it is not yet developed for prognostication for primary or secondary breast cancer development utilizing at-risk breast tissue. Both estrogen receptor a (ER) and aromatase overexpression have been linked to human breast cancer. Herein, conditional genetically engineered mouse models of estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) were used to show that induction of Esr1 overexpression just before or with reproductive senescence and maintained through age 30 months resulted in significantly higher prevalence of estrogen receptor-positive adenocarcinomas than CYP19A1 overexpression. All adenocarci-nomas tested showed high percentages of ER thorn cells. Mammary cancer development was preceded by a persistent proliferative transcriptome risk signature initiated within 1 week of transgene induction that showed parallels to the Prosigna/Prediction Analysis of Microarray 50 human prognostic signature for early -stage human ER thorn breast cancer. CYP19A1 mice also developed ER thorn mammary cancers, but histology was more divided between adenocarcinoma and adenosquamous, with one ER- adenocarcinoma. Results demonstrate that, like humans, generation of ER thorn adenocarcinoma in mice was facilitated by aging mice past the age of reproductive senescence. Esr1 overexpression was associated with a proliferative estrogen pathway-linked signature that preceded appearance of ER thorn mammary adenocarcinomas. (Am J Pathol 2023, 193: 103-120; https://doi.org/10.1016/j.ajpath.2022.09.008)

Automated summary

Age is a risk factor for estrogen receptor-positive breast cancer, especially after menopause. The study used genetically engineered mouse models to show that overexpression of estrogen receptor 1 (Esr1) before or during reproductive senescence resulted in a higher prevalence of estrogen receptor-positive adenocarcinomas compared to overexpression of cytochrome P450 family 19 subfamily A member 1 (CYP19A1). The results demonstrate the importance of aging and estrogen pathway-linked signatures in the development of ER-positive mammary adenocarcinomas.