Abstract P4-02-12: Genomic Evolution of Endocrine-Resistant Breast Cancer Cell Lines Reveals Molecular Aberrations Consistent with Biological Phenotype

Abstract

Abstract Suppression of estrogen synthesis using aromatase inhibitors (AIs) is highly effective in the treatment of postmenopausal women with estrogen receptor alpha-positive (ER+) breast cancer. Third generation AIs are superior to adjuvant tamoxifen resulting in improved disease-free survival and a lower incidence of side effects. Unfortunately, one of the consequences of long-term estrogen deprivation or exhaustive endocrine therapy is the development of drug resistance. We and others have shown that acquisition of resistance to long term estrogen deprivation or to selective estrogen receptor modulators (SERMs) in breast cancer cells is accompanied by an increase in malignant cell behavior. The Jordan Laboratory has developed in vitro and in vivo models of endocrine-resistant breast cancer that mimic pathobiology observed in anti-hormone refractory breast tumors. MCF-7:5C and MCF-7:2A are two ER+ human breast cancer cell lines derived from long term estrogen deprivation of hormone-dependent MCF-7 cells. MCF-7:TAM2 and MCF-7:RAL2 are also ER+ derivatives of MCF-7 that are resistant to tamoxifen and raloxifene, respectively. These models of resistance share several phenotypic and molecular characteristics, which differ dramatically from the isogenic parental line. Differences include robust growth in estrogen-deprived medium, mesenchymal morphology, and increased invasiveness and motility in vitro. They also exhibit elevated AKT activity, loss of E-cadherin, and additional molecular markers consistent with malignant progression. We have conducted an array-based genomic study to elucidate molecular mechanisms associated with development of endocrine resistance in each model. We observed a high degree of genomic evolution in all endocrine-resistant models. Several regions of common genomic aberration were observed in the MCF-7:5C and MCF-7:2A cells that indicate significant deregulation of glycolysis and glucose metabolism, a metabolic process known to be driven by activated AKT. Gene ontology analysis of genes differentially expressed by both MCF-7:5C and MCF-7:2A also highlighted deregulated AKT signaling and cell cycle control in these cells. Interestingly, amplification of the estrogen receptor 1 (ESR1) gene, which encodes estrogen receptor alpha, was observed in MCF-7:5C and MCF-7:2A models but not in the SERM-resistant models supporting diversity underlying mechanisms of endocrine resistance depending on therapies used. This study indicates that biological drivers of endocrine resistance can be identified using integrated genomic and bioinformatic approaches. We are currently prioritizing the likely molecular drivers of endocrine-resistant disease using high throughput RNAi technology. Grant support: Department of Defense Breast Program under award number BC050277 Center of Excellence (V.C. Jordan). Views and opinions of and endorsements by the author(s) do not reflect those of the U.S. Army or the Department of Defense. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-12.