Abstract
Abstract Background: Aromatase inhibitors (AIs) are effective in treating postmenopausal patients with estrogen receptor (ER)-positive breast cancer. However, resistance to endocrine therapies remains a major problem in the management of ER-positive breast cancer. Recently, histone deacetylase inhibitors (HDACis) show promise as cancer therapeutics, but the full scope of their utility remains unknown. Experimental Design: In order to search for critical genes in developing resistance to AI, a microarray study was performed on AI resistant cells derived from MCF-7aro cells that overexpress aromatase and on AI resistant tumors from our mouse experiments. Moreover, using MCF-7aro cells that are resistant to anastrozole (Ana-R), letrozole (Let-R), and exemestane (Exe-R), as well as LTEDaro, we evaluated the significance of NFKB1 and several regulatory genes in AI resistance, and the anti-NFκB1 activity of HDACi LBH589 in vitro and in vivo. Results: Significant changes (Fold change cutoff > 1.5, false discovery rate < 0.05) in the expression levels of 22 genes among three networks were identified from microarray analysis of our in vitro and in vivo models of acquired AI resistance. NFKB1 is a key player in one of three networks, including 11 genes, and is functionally up-regulated in all AI resistant cells. NFκB1 knockdown suppresses the proliferation of AI resistant cells more than that of MCF-7aro cells. Moreover, AI resistant cell lines are highly sensitive to LBH589 treatment and apoptosis is induced in these cell lines. LBH589 suppressed NFκB1 as demonstrated at both the mRNA and protein levels in LTEDaro and other AI resistant cell lines. Furthermore, the LBH589 treatment abrogated tumor growth in mice, and was associated with significant decreased levels of NFKB1 in tumors. Conclusions: Our findings provide new insights into how the NFκB1-mediated networks play roles in AI resistance, and strongly support that LBH589 offers a novel therapeutic strategy for patients with AI resistant breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-05.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
