Responsiveness of Brca1 and Trp53 Deficiency-Induced Mammary Preneoplasia to Selective Estrogen Modulators versus an Aromatase Inhibitor in Mus musculus

Abstract

An intervention study initiated at age 4 months compared the impact of tamoxifen (25 mg), raloxifene (22.5 mg), and letrozole (2.5 mg) administered by 60-day release subcutaneous pellet on mammary preneoplasia prevalence at age 6 months in conditional genetically engineered mouse models with different Breast cancer 1 (Brca1) gene dosages targeted to mammary epithelial cells and germline Tumor protein P53 (Trp53) haploinsufficiency (10-16/cohort). The proportion of unexposed control mice demonstrating mammary preneoplasia at age 6 months was highest in Brca1^{fl11/fl11/Cre/p53-/+} (54%) mice followed by Brca1^{WT/fl11/Cre/p53-/+} mice (30%). By age 12 months, invasive mammary cancers appeared in 80% of Brca1^{fl11/fl11/Cre/p53-/+} and 42% of Brca1^{WT/fl11/Cre/p53-/+} control unexposed mice. The spectrum of cancer histology was similar in both models without somatic mutation of the nongenetically engineered Brca1, Trp53, Brca2, or Death-associated protein kinase 3 (Dapk3) alleles. Two-month exposure to tamoxifen, raloxifene, and letrozole significantly reduced estrogen-mediated tertiary branching by 65%, 71%, and 78%, respectively, in Brca1^{fl11/fl11/Cre/p53-/+} mice at age 6 months. However, only letrozole significantly reduced hyperplastic alveolar nodules (HAN) prevalence (by 52%) and number (by 30%) and invasive cancer appeared despite tamoxifen exposure. In contrast, tamoxifen significantly reduced HAN number by 95% in Brca1^{WT/fl11/Cre/p53-/+} mice. Control mice with varying combinations of the different genetically modified alleles and MMTV-Cre transgene demonstrated that the combination of Brca1 insufficiency and Trp53 haploinsufficiency was required for appearance of preneoplasia and no individual genetic alteration confounded the response to tamoxifen. In summary, although specific antihormonal approaches showed effectiveness, with Brca1 gene dosage implicated as a possible modifying variable, more effective chemopreventive approaches for Brca1 mutation-induced cancer may require alternative and/or additional agents. Cancer Prev Res; 10(4); 244-54. ©2017 AACR.