Abstract B260: Wnt signaling, triple-negative breast cancer, and green tea.

Abstract

Abstract Background and Goals: Triple negative breast cancer (TNBC) represents 15-20% of sporadic breast cancers, lacks ER, PR, and HER2 overexpression - and thus has no targeted treatment options. TNBC is a clinically challenging subtype with exceptionally poor prognosis, high recurrence and metastases and currently represents an unmet medical need. A critical aspect to improving the outcome for TNBC and other breast cancer patients is the prevention and/or treatment of distant metastases, especially to brain. Another major limitation of TNBC treatment is that most current drugs do not cross the blood-brain barrier to target fatal brain metastases, so novel therapeutic approaches are urgently needed. Results: TNBC have a Wnt signaling etiology and our recent work shows that HBP1 (a transcriptional repressor that suppresses Wnt signaling) was decreased in TNBC. Specifically, we showed that the HBP1 gene was mutated or reduced in invasive breast cancers. The under-expression of two Wnt pathways inhibitors (SFRP1 and HBP1) predicted an exceptionally poor prognosis. We sought to identify new therapeutic strategies aimed at TNBC and at decreasing Wnt signaling. Here, we investigated a combined regimen of the green tea polyphenol epigallocatechin gallate (EGCG) and of decitabine (DAC) that we reasoned might be effective at elevating SFRP1 and HBP1 to reverse a poor prognosis. We reported that EGCG decreased Wnt signaling in vitro by elevating HBP1. EGCG is in numerous clinical trials for breast and other cancers. Decitabine is an inhibitor of DNA methylation and is FDA-approved for hematologic malignancies. Thus, new pre-clinical studies have excellent potential to re-purpose existing drugs for TNBC. The combined regimen of EGCG/DAC significantly reduced TNBC tumorigenesis in two orthotopic TNBC tumor xenograft models (MDA-MB231 and Sum149). The inhibition by EGCG/DAC treatment correlated with reduced Wnt signaling and with the elevated SFRP1 and HBP1 gene expression. Importantly, a stable knockdown of either HBP1 or SFRP1 resulted in larger TNBC tumors that were now refractory to EGCG/DAC treatment. These data suggests that the decreased Wnt signaling and elevation of HBP1 or SFRP1 were critical factors to the efficacy of EGCG/DAC. Finally, EGCG/DAC treatment was effective at reducing brain metastases initiated from the mammary orthotopic site in a variant MDA-MB231TNBC tumor model. Conclusions: Our studies indicated that a combined regimen of EGCG and DAC decreased Wnt signaling and reduced TNBC tumorigenesis and resulting brain metastases in pre-clinical models. Thus, EGCG/DAC appears to uniquely cross the blood-brain barrier to reduce the otherwise fatal brain metastases, likely by reducing Wnt signalling. Together, EGCG/DAC may be an excellent therapeutic combination for clinical trials aimed at improving TNBC patient outcomes. (Supported by NIH, AICR, the Komen Foundation, and DOD to ASY, GES, and JB. MC was supported by NIH Hematology-Oncology Training Grant to Tufts Medical Center). Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B260. Citation Format: Amy S. Yee, Kurtz Eric Paulson, Maricel Castaner, Helen Uong, Nora Minerva, Kai Wang, Kelsey Gilchrist, Maria Choi, Gail E. Sonenshein, Jim Baleja. Wnt signaling, triple-negative breast cancer, and green tea. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B260.