Abstract A34: A mechanism for acquired resistance to estrogen deprivation in breast cancer cells

Abstract

Abstract Endocrine therapies that target the proliferative effect of 17β-estradiol (17βE2) through estrogen receptor α (ERα) are the most effective form of systemic treatment of ERα-positive breast cancer. Nevertheless, through mechanisms that are not fully understood, most tumors that initially respond to therapy will recur. The long-term estrogen deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibition (AI) in postmenopausal women. To comprehensively elucidate this resistance, genomic, transcriptomic and molecular analyses were integrated into the time course of MCF7-LTED adaptation. Extensive and dynamic genomic changes were observed, including amplification of the ESR1 locus linked to an increase in ERα and its non-genomic role. Dynamic transcriptomic profiles were also observed that significantly correlated with genomic changes and that were influenced by transcription factors known to be involved in acquired resistance (IRF-1) and cell proliferation (E2F1) but not by canonical ERα genomic function. Evaluation of MCF7-LTED profiles association with pathological and clinical data shown consistent correlations with ERα-negative tumor status, letrozole effects and recurrence after tamoxifen treatment. This study describes the coordinated genomic, transcriptomic and molecular changes that mediate acquired resistance to endocrine therapies, suggesting a key role for the non-genomic function of ERα. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A34