Preclinical modeling of endocrine response: a combination therapy approach with the ERβ agonist, diarryl propionitrile and letrozole restores sensitivity to letrozole-resistant breast cancer cells.

Abstract

#17 The majority of breast cancer patients are postmenopausal women with estrogen receptor-positive (ER+) tumors. Approximately 66% of breast carcinomas contain aromatase. Aromatase inhibitors are proving to be more effective than tamoxifen in the treatment of postmenopausal women with ER+ breast cancer. However, the development of resistance to treatment is a concern. The transition of the ER+ tumors from a responsive to unresponsive state is associated with different molecular pathways. We have therefore investigated the properties of resistance that develops in response to the aromatase inhibitor letrozole in the preclinical MCF-7-aromatase xenograft animal model following long-term treatment with letrozole by using the derived letrozole-resistant MCF-7-aromatase LTLTca breast cancer cells. The combination treatment of letrozole and the ERβ agonist diarryl propionitrile (DPN) restored sensitivity to letrozole in the letrozole-resistant LTLTca cells. Studies from our group using this postmenopausal breast cancer preclinical model clearly showed the therapeutic advantage of the ERβ agonist in overcoming unresponsiveness to letrozole. A 67% reduction in tumour size was observed in the group of animals bearing the letrozole-resistant LTLTca tumors that received the combination of letrozole and DPN. A novel delivery method using letrozole-DPN nanoparticles showed enhanced sensitivity (∼80%) to the combination nanoparticles. Letrozole was found to be relatively ineffective in these animals with only a 36% reduction in tumor size with tumors having a mean tumor weight of 0.95g by the end of four weeks of treatment. Biochemical analysis showed a reduction in the tumor aromatase enzyme levels in mice treated with letrozole + DPN when compared to letrozole alone. QRT-PCR as well as protein analysis studies of the letrozole-resistant LTLTca tumors showed a decrease in P27 levels and elevated expression levels of HER-2. Expression levels of cyclin D1 and the ERα to ERb ratio was higher in the untreated letrozole-resistant tumors compared to tumors that responded to the combination therapy. These findings provide further support for the development and testing of novel therapeutic approaches for selective regulation of ER-dependent (ERα and β) actions. Combination treatments involving agents that modulate ERβ activity may provide therapeutic advantage in the treatment, for overcoming resistance to estrogen-ablation and prevention of breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 17.

Management of Aromatase Inhibitor-Resistant Disease with Estrogen, Selective Estrogen Receptor Down-Regulators, and Other Agents

“…In a preclinical model, acquired resistance to long-term letrozole was overcome by a combination of letrozole and the ER agonist diarryl propionitrile [31].…”