Molecular Effect of EGCG/DAC Chemotherapy on Wnt Signaling in Triple Negative Breast Cancer.
Hafez, Salwa.
2016
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Abstract: Triple negative breast cancer (TNBC) cannot be treated with the conventional targeted breast cancer therapies. Thus, investigating potential signaling pathways and specific targets is highly desired. One of those pathways is Wnt/-catenin signaling pathway, which is known to have elevated activity in TNBC, and that may contribute to the invasiveness of this type of cancer. HBP1 is a suppr... read moreessor gene that inhibits Wnt/- catenin signaling and blocks Wnt targeted genes. Moreover, deletion, mutation or decreased expression of the HBP1 gene is associated with more aggressive breast tumors, especially triple negative breast cancer (TNBC). DAC (5-aza-2'-deoxycytidine) is an inhibitor of DNA methylation through inhibiting DNA Methyltransferase 1 (DNMT1), and treatment with DAC restores epigenetically silenced genes such as HBP1, leading to increased expression. In addition, EGCG (epigallocatechin 3-gallate) is known to induce HBP1 expression levels through an RNA stabilization mechanism. The Yee lab designed the combinational drug regimen EGCG/DAC that acts synergistically to increase levels of HBP1 (Wnt inhibitors) leading to suppression of Wnt/-catenin signaling. Also, decreased expression of HBP1 has been associated with an increase in both migration and invasion of breast cancer cells in culture. We examined the efficacy of EGCG/DAC using an RNAseq and bioinformatics analysis of treated and untreated TNBC tumors, which suggests that EGCG/DAC appeared to inhibit multiple biological functions, including cell movement and cell growth, while also stimulating other biological functions such as apoptosis. Also, to further validate the molecular effect of EGCG/DAC we used both in vitro and in vivo experiments. We hypothesized that EGCG/DAC alters HBP1 expression through changes in HBP1 gene DNA/chromatin methylation. As stated, one of the observations from the bioinformatics analysis of the EGCG/DAC RNAseq is a decrease in invasion and metastasis signatures.
Thesis (M.S.)--Tufts University, 2016.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisors: Amy Yee, and Eric Paulson.
Keyword: Pharmacology.read less - ID:
- 5712mk59b
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