Abstract 1738: Histone deacetylase inhibitor mediated reversal of acquired endocrine therapy resistance in breast cancer cell lines
Authors: Raha Paromita , Thomas Scott , Thurn K Ted , Munster Pamela 
Published: July 2012

Abstract
Although nearly 70% of breast cancers are estrogen receptor (ER) positive, endocrine therapy using the selective ER modulator tamoxifen or the selective ER down regulator fulvestrant have proved to be beneficial in less than 50% of these patients. Moreover, most ER positive patients that initially respond to tamoxifen eventually acquire resistance. Numerous studies have focused on determining the mechanism of anti-estrogen resistance which involve cellular changes such as variation in uptake/metabolism of tamoxifen, expression of altered ER proteins, ligand-independent ER activation, loss of ER expression and/or variation in recruitment of cofactors and altered cross-talk with other growth factor signaling pathways.
Recently, an alternative strategy to modulate ER signaling has been the use of histone deacetylase (HDAC) inhibitors. Preclinical studies have shown that with the addition of HDAC inhibitors, the anti-tumor activity of tamoxifen is potentiated. In these cells, apoptotic cell death is induced, which cannot be rescued by estrogen, indicating the potential to reverse hormone therapy resistance, a strategy currently being evaluated in several clinical trials.
Our laboratory is interested in exploring the potential of HDAC inhibition for the reversal of anti-estrogen resistance in ER-positive breast cancer. To this end, we have generated several MCF-7 cell lines resistant to various levels of tamoxifen; up to 10 micromolar. Our preliminary data demonstrate the addition of an HDAC inhibitor to tamoxifen reverses resistance. Significant effects on proliferation and viability are observed in these cells with clinically relevant concentrations of pan-HDAC inhibitors. Furthermore, with the addition of an HDAC inhibitor to tamoxifen, colony formation is attenuated. Initial characterization of these resistant cells indicated a several fold higher growth rate than the parental cells but a similar growth rate in presence and absence of the ligand estrogen, suggesting the possibility of loss of estrogen-dependence. Both the parental and resistant cells, in presence of estrogen, show a stabilization of the estrogen receptor protein by tamoxifen, which is not altered by the HDACi, suggesting an effect that goes beyond modulation of ER protein level. Tamoxifen or the combination in the resistant cells do not decrease Cyclin D1 protein level as is seen in parental cells, suggesting the involvement of pathways not involving ER.
Our previous data using siRNA against HDAC2 indicate sensitization of ER positive breast cancer cells to tamoxifen-mediated apoptosis suggesting the importance of HDAC2. We plan to study the importance of ER, in resistant cells with varied ER status, in mediating the hormone therapy response and to identify the potential involvement of other signaling pathways, using both HDAC inhibitors and selectively depleting HDAC2.
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 1738. doi:10.1158/1538-7445.AM2011-1738