Abstract 3843: Targeting FACT complex suppresses mammary tumorigenesis in Her2/neu transgenic mice

Abstract

Abstract We have recently found that expression of Facilitates Chromatin Transcription (FACT) complex consisting of SSRP1 and SPT16 protein subunits is elevated in many types of cancer comparing with normal tissues. Moreover, survival of tumor cell, but not normal cells is significantly compromised upon genetic knockdown of any of the FACT subunits. In our recent studies we have shown that FACT is essential for the transcriptional activity of NF-κB and Heat Shock Factor 1 and identified small molecules that inhibit activity of both transcription factors by causing functional inactivation of FACT. Since both NF-kB and HSF1 are activated in the process of transformation, we proposed that FACT may be involved in tumor transformation and that inhibition of FACT activity may prevent or reduce tumorigenesis. Objectives of our study were: (i) to check if FACT level is changed in the process of oncogene-induced transformation in vitro and in vivo; and (ii) to test safety and efficacy of anti-FACT therapy with Curaxin-137 in prevention of tumor formation in mice prone to cancer due to oncogene overexpression. We used in vitro (Ha-ras12V) and in vivo (MMTV-neu transgenic mouse model) models of transformation to monitor changes in FACT subunits. We treated the MMTV-neu transgenic mice, in which mammary carcinomas are spontaneously developed due to estrogen receptor-regulated expression of the Her2 proto-oncogene, with Curaxin-137 to determine whether the drug has any toxic effect on normal tissues and/or impact on mammary carcinogenesis. Expression of FACT was elevated in the process of transformation in all models tested. Chronic administration of Curaxin-137 to MMTV-neu mice at doses not having any toxic effect, inhibited tumor onset, delayed tumor progression, and prolonged survival of mice in a dose-dependent manner. Curaxin-137 induced much stronger changes in FACT in tumors than in normal organs, expressing FACT (spleen). Thus, Curaxin-137 may be considered as a potential preventive and/or early stage therapeutic agent for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3843. doi:1538-7445.AM2012-3843