Abstract 2297: ERβ agonists reduce letrozole resistant breast cancer cell growth and diminish aromatase expression and activity

Abstract

Abstract Aromatase inhibitors (AI) have shown efficacy against estrogen receptor (ER) positive breast cancer; however, development of resistance to AI is a major concern. The need to develop therapeutic agents that overcome AI resistance is urgent. We investigated whether synthetic and natural selective ERβ agonists restored sensitivity to AI and anti-estrogens in hormone resistant breast cancer cells. Our data suggest that ERβ agonists such as DPN (a synthetic compound) and plant derived Nyasol, Liquiritigenin, and MF101 (Menerba) ERβ agonists may restore sensitivity against resistance by the current drugs. Natural ERβ agonists in combination with AI reduced cell proliferation in MCF7/ARO (overexpressing aromatase), MCF7/HER2 (overexpressing Her2/neu) LTLT-Ca (letrozole resistant), MCF7/TAM (tamoxifen resistant), SKBR3, and T47D breast cancer cells by 70 % to 90% when compared with DPN/AI combination. Our Western blot and RT-PCR analyses showed that combination treatment with natural ERβ agonist in combination with AI resulted in decreased levels of ERα, Cyclin D1, TNF-α, IL-6 and increased ERβ levels in LTLT-Ca and MCF7/ARO cells. In addition, aromatase expression and activity were decreased due to ERβ agonists/AI combination treatment. The activity of aromatase promoter 1.3, which is activated in breast cancer, was found to be down regulated with Nyasol, Liquiritigenin and MF101 combinations with AI when compared to single compounds in various breast cancer cells. Decreased promoter 1.3 activity is consistent with the combination-treatment decrease in the expression of inflammatory cytokines known to induce this promoter (e.g., IL-6). Our data suggest that inhibition of aromatase expression/activity by natural ERβ agonists (in combination with AI) may be a factor in overcoming AI-resistant breast cancer cell growth by these drugs. Our data also suggest that modulation of inflammatory cytokines may be factors by which ERβ agonists may influence aromatase expression and sensitizing AI-resistant breast cancer to AI therapy. Further work is required to understand the mechanistic aspects of this regulation and to advance natural ERβ agonists to the clinical treatment of AI-resistant breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2297. doi:10.1158/1538-7445.AM2011-2297