Gene expression changes during acquired resistance to tamoxifen and letrozole; a preclinical model of post-menopausal breast cancer

Abstract

9620 Background: Most metastatic breast cancers initially respond to hormonal treatment but all become resistant to these treatments over time. The genetic events that occur during acquired resistance are unknown. To examine the gene expression changes during acquired hormonal resistance, we used a model that mimics ER positive breast cancers in the post-menopausal setting with the tumours responsive to both Tamoxifen (TAM) and aromatase inhibitors. Tumours were analyzed with high density cDNA arrays to identify genes associated with TAM and Letrozole (LET) resistance. Methods: Aromatase-transfected MCF-7Ca human breast cancer cells were grown as tumour xenografts in female ovariectomized athymic nude mice in which an androstenedione supplement was converted to estrogen to stimulate tumour growth. When tumour volume was approximately 300 mm3, the animals were grouped (4 groups, n=20) for continued supplementation with androstenedione (Δ4A) only (control), Letrozole(an aromatase inhibitor) 10 μg/day + Δ4A, TAM 100 μg/day + Δ4A, or vehicle. Animals were sacrificed and tumours retained at various time points during the development of hormone resistance. Tumour RNA samples were compared to reference RNA from Stratagene and incubated with 14K microarrays (Array-Ready Oligo Set, Qiagen). Expression results were analyzed with Genespring 6.1 (Silicon Genetics). Results: We have identified 35 TAM-resistant and 30 LET-resistant associated genes that are over-expressed by at least 2-fold and significant by ANOVA. They include; lysyl oxidase-like 2, Homo sapien partial N-myc, and TNF superfamily member 12. Her 2 neu was not over-expressed in acquired hormone resistance (TAM or LET). ER coactivators and corepressors including nuclear receptor coactivator 1and p300/CBP were altered in TAM resistance. At the meeting we will present data on the observed expression changes. We are collecting biopsies from patients to validate these observations Conclusions: Chromatin remodeling genes are among the genes that are over-expressed in acquired TAM- and LET-resistance. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis