Comparison of tamoxifen and letrozole response in mammary preneoplasia of ER and aromatase over-expressing mice defines an immune-associated gene signature linked to tamoxifen resistance

To investigate response or resistance to endocrine therapy, mice with targeted over-expression of Esr1 or CYP19A1 to mammary epithelial cells were employed, representing two direct pathophysiological interventions in estrogen pathway signaling. Both Esr1 and CYP19A1 over-expressing mice responded to letrozole with reduced HAN prevalence and decreased mammary epithelial cell proliferation. CYP19A1 over-expressing mice were tamoxifen-sensitive but Esr1 over-expressing mice were tamoxifen-resistant. Increased ER expression occurred with tamoxifen resistance but no consistent changes in progesterone receptor, pSTAT3, pSTAT5, cyclin D1 or cyclin E levels in association with response or resistance was found. RNA-seq was employed to seek a transcriptome predictive of tamoxifen resistance using these models and a second tamoxifen-resistant model, BRCA1 deficient/Trp53 haploinsufficient mice. Sixty-eight genes associated with immune system processing were upregulated in tamoxifen-resistant Esr1 and Brca1 deficient mice whereas genes related to aromatic compound metabolic process were upregulated in tamoxifen-sensitive CYP19A1 mice. Interferon Regulatory Factor 7 was identified as a key transcription factor regulating these 68 immune processing genes. Two loci encoding novel transcripts with high homology to human IGLL1 were uniquely upregulated in the tamoxifen-resistant models. Letrozole proved to be a successful alternative to tamoxifen. Further study of transcriptional changes associated with tamoxifen resistance including immune-related genes could expand our mechanistic understanding and lead to biomarkers predictive of escape or response to endocrine therapies. Single- and paired-end mRNA-seq with WT, Esr1 over-expressing (CERM, tetracycline-operator(tet-op)-Esr1MMTV-rtTA), CYP19A1 over-expressing (AROM, tet-op-CYP19A1MMTV-rtTA) and Brca1 KO (BRCA, Brca1fl11/fl11/MMTV-Cre/p53+/- ) mice