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/β-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... read moresuppressor gene that inhibits Wnt/β- 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/β-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
- Component ID:
- tufts:20354
- To Cite:
- DCA Citation Guide EndNote
