Abstract P4-11-01: Effect of letrozole is superior to tamoxifen in limiting preneoplasia in both ERa and aromatase over-expressing mice
Authors: Diaz-Cruz ES , Dabydeen SA , Al-Kharboosh R , Wang W , Furth PA 
Published: August 2014

Background: Breast cancer develops as genetic changes give rise to preneoplastic lesions, which may or may not progress to invasive breast cancer. Studies suggest that estrogens may promote this process. Targeted over-expression of both estrogen receptor (Esr1) and aromatase (CYP19A1) to mammary epithelial cells (MECs) of genetically engineered mice results in the development of mammary hyperplasia and invasive cancer. Both of these genetic interventions lead to altered estrogen signaling pathways with increased expression levels of progesterone receptor (PGR) and cyclin D1. Tamoxifen is currently the only FDA-approved drug for chemoprevention of invasive breast cancer in premenopausal high-risk women but while effective it does not absolutely prevent cancer development.

Purpose: Test the impact of letrozole and tamoxifen in both tet-op-CYP19A1/MMTV-rtTA mice and tet-op-Esr1/MMTV-rtTA.

Methods: Female tet-op-CYP19A1/MMTV-rtTA and tet-op-Esr1/MMTV-rtTA mice were implanted subcutaneously with a pellet containing either letrozole 2.5mg (60-day release), tamoxifen 25mg (60-day release), or placebo at age 10m. Mice were necropsied at age 12m and mammary tissue collected for morphological, histological, and protein expression studies. Whole mounts and hematoxylin and eosin stained slides were used to evaluate growth abnormalities, hyperplastic alveolar nodules (HANs) or cancer. Immunohistochemistry and western blot analyses were used to compare and quantitate changes in protein expression.

Results: Letrozole treatment resulted in no HAN detection in both Esr1 and CYP19A1 over-expressing mice. Tamoxifen reduced HAN prevalence to 14 (compared to 60%) in CYP19A1 over-expressing mice; HAN prevalence persisted in 56% (as compared to 67%) in Esr1 over-expressing mice. The reduction in preneoplasia prevalence in letrozole treated mice was accompanied by a statistically significant reduction in the proliferative index in both CYP19A1 and Esr1 over-expressing mice. However, reductions found following tamoxifen exposure were not statistically significant. Letrozole significantly reduced the percentage of ERα positive nuclei and the modified Allred score for cyclin D1 in CYP19A1 over-expressing mice, but not in Esr1 over-expressing mice as compared to control mice. In Esr1 over-expressing mice tamoxifen exposure was associated with a significant increase in the percentage of ERα positive nuclei that was not seen in the CYP19A1 over-expressing mice. PGR expression differences were not statistically significant for either treated group.

Conclusions: The impact of letrozole was greater than tamoxifen in reducing prevalence of preneoplasia and MEC proliferation rates in both ERα and aromatase over-expressing mice. These results suggest that letrozole should be considered as a chemopreventive agent based on individual estrogen signaling prognostic factors.

Support: P30CA051008, RO1CA112176, T32CA009686-15, KG080359. Support: P30CA051008, RO1CA112176, T32CA009686-15, KG080359. Content solely responsibility of authors and does not necessarily represent official NCI/NIH views.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-11-01.