Abstract 4693: Inhibition of BET bromodomain targets PTEN positive endometrioid endometrial cancers

Abstract

Abstract Introduction: Endometrioid endometrial cancers (EEC) are commonly characterized by PTEN mutations and loss of function. JQ-1 is a selective small-molecule BET bromodomain inhibitor, and BET inhibition by JQ-1 leads to the downregulation of c-Myc transcription. Thus, JQ-1 functions as a novel c-Myc inhibitor and has been found to potently suppress tumor growth in many human cancers. Given the known interactions between c-Myc and the PI3K/Akt/mTOR pathway, we aim to assess the impact of JQ-1 on human EEC cell lines and further explore the mechanism underlying cellular resistance to JQ-1 treatment. Methods: Six EEC cancer cell lines were used in this study. Cell proliferation was assessed by MTT assay and colony formation assay after exposure to JQ-1. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by Annexin V-FITC assay. Expression of c-Myc, PTEN, phosphorylated-Akt, phosphorylated-S6, cyclins and cyclin-dependent kinases (CDKs) was detected by Western blotting analysis. Up- or down-regulation of PTEN was achieved by stable transfection with pcDNA3.1-PTEN or shRNA-PTEN, respectively. Results: JQ-1 significantly suppressed proliferation in the EEC cell lines that were PTEN positive (IC50=75 nM for HEC-1A, 550 nM for KLE and 1000 nM for ECC-1), but not in those that were PTEN negative (IC50>10000 nM for Ishikawa, AN3CA and RL 95-2). JQ-1 induced G1 cell cycle arrest in the PTEN positive HEC-1A and KLE cell lines, but had minimal effects on cell cycle progression in the PTEN negative Ishikawa and AN3CA cell lines. Western blotting analysis demonstrated that JQ-1 suppressed the expression of c-Myc, cyclins and CDKs. JQ-1 up-regulated PTEN expression and decreased phosphorylation of downstream targets of the PI3K/Akt/mTOR signaling pathway, including Akt and S6. Knock-down of PTEN led to cellular resistance to JQ-1 in the HEC-1A and KLE cells, while over-expression of PTEN sensitized Ishikawa and AN3CA cells to JQ-1 treatment. Conclusions: We find that JQ-1 significantly suppressed cellular proliferation through G1 cell cycle arrest in the EEC cell lines with abundant PTEN expression. Knock-down of PTEN caused cellular resistance while over-expression of PTEN sensitized EEC cells to JQ-1. This evidence suggests that JQ-1 may be a promising targeted therapy for EEC patients with PTEN positive tumors. Note: This abstract was not presented at the meeting. Citation Format: Haifeng Qiu, Amanda Jackson, Joshua Kilgore, Chunxiao Zhou, Victoria Lin Bae-Jump. Inhibition of BET bromodomain targets PTEN positive endometrioid endometrial cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4693. doi:10.1158/1538-7445.AM2014-4693