Abstract 2014: An estrogen receptor - centered network for probing anti-estrogen drug resistance with siRNA screening technology
Rochelle E. Nasto, Ilya G. Serebriiskii, Sandra A. Jablonski, Michael D. Johnson, Robert C. Clarke, Louis M. Weiner, Erica A. Golemis · Cancer Research · 2010
Abstract De novo and acquired drug resistance pose significant problems for the effective treatment of estrogen-receptor (ER) positive breast cancers. We hypothesized that changes in the action of proteins interacting with core components of the estrogen response machinery may be responsible for such resistance, and that inhibition of these proteins may modulate response to hormonal therapies. To test this idea, we created a 631 gene network using ERα (ESR1), ERβ (ESR2), estrogen related receptors α (ESRRA) and γ (ESRRG), and aromatase as seed genes. The addition of genes to the network was selectively based on connectedness to the 5 seed genes. We used a set of bioinformatic resources including protein-protein interactions (PPIs), protein complexes, canonical pathways and estrogen responsive genes, to generate candidates for insertion into this network. An siRNA library has been developed from these 631 genes, for use in screening of breast cancer cell lines. Our primary goal is to identify networks of candidate genes involved in resistance to estrogen pathway-targeted drugs, corresponding to genes that reduce cell viability specifically in the presence of the hormonal therapies fulvestrant and tamoxifen. We have used MCF7/LCC1 cells (tamoxifen sensitive/fulvestrant sensitive), MCF7/LCC2 (tamoxifen resistant/fulvestrant sensitive) and MCF7/LCC9 (tamoxifen resistant/ fulvestrant resistant) cell lines as syngeneic models with varying drug resistance profiles for these experiments. In addition, we are identifying genes that differentially affect the intrinsic viability of these cell lines, and thus should illuminate the mechanism of their resistance to hormonal therapies. Our goal is to elucidate a network of regulators of anti-estrogen resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2014.