Abstract LB-95: Estrogen receptor mRNA-directed therapy for triple-negative breast cancer
Authors: Roemeling Christina A. von , Marlow Laura A. , Miller James , Mathias Adam , Dawson Louis , Harrison Steadman , Hollister Beth A. , Radisky Derek C. , Copland John Alton 
Published: May 2015

Introduction: A significant number of histologically triple negative breast cancer (TNBC) cells express substantial estrogen receptor (ER) mRNA but do not express ER protein as a result of rapid proteolytic degradation. Here we assessed whether proteasome inhibitors could sensitize such cells to tamoxifen-induced growth suppression. Methods: Data from the Katzenellenbogen laboratory elegantly demonstrate that in high ER mRNA MDA-MB-468 cells, ER protein is rapidly degraded via proteosomal degradation (Bhatt et al. MCB, 2012).Utilizing established human TNBC cell lines that express high ER mRNA (BT-20, MDA-MB-468, and newly established human TNBC cell lines from our laboratory MCJB2 and MCJB11), we defined a therapeutic strategy using the proteasome inhibitor carfilzomib in combination with the antiestrogen tamoxifen that demonstrates antitumor synergy. Results: We found that administration of carfilzomib in TNBC cell lines with high ER mRNA restored ER protein expression, and that combining this treatment with tamoxifen treatment led to enhanced growth suppression. We found that the TNBC MDA-MB-231 cells, which express no ER mRNA, show some growth suppression, but that tamoxifen provided no further growth suppression with these cells. We have previously shown that combined epigenetic therapy [methyltransferase inhibitor (decitabine) plus a histone deacetylase inhibitor (HDACi; romidepsin)] provided antitumor synergy in MDA-MB-231 cells via upregulation of the soluble Wnt suppressor, secreted frizzled protein 1 (sFRP1; Cooper et al. CCR, 2012). In addition, we show that this epigenetic therapy restores silenced ER mRNA and protein levels in MDA-MB-231 cells, and that combination of this epigenetic therapy with tamoxifen in MDA-MB-231 cells led to enhanced growth suppression by tamoxifen. We are currently testing these therapeutic strategies in vivo using established TNBC cell lines and our newly developed patient derived xenograft (PDX) mouse models that express either ERhigh or ERlow mRNA. Conclusions: If validated in animal models, we propose that ER mRNA expression level in TNBC patients could guide therapeutic choice, whereby, ERlow mRNA TNBC tumors could respond to epigenetic therapy followed by antiestrogen while ERhigh mRNA TNBC tumors could respond to a proteosome inhibitor followed by antiestrogen therapy. These results identify a novel epigenetic biomarker as predictive of therapeutic response.

Citation Format: Christina A. von Roemeling, Laura A. Marlow, James Miller, Adam Mathias, Louis Dawson, Steadman Harrison, Beth A. Hollister, Derek C. Radisky, John Alton Copland. Estrogen receptor mRNA-directed therapy for triple-negative breast cancer. [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 LB-95. doi:10.1158/1538-7445.AM2014-LB-95