Document Type

Theses, Masters

Rights

This item is available under a Creative Commons License for non-commercial use only

Disciplines

Cell biology,

Publication Details

Thesis carried out in conjunction with FAS Science Challenge, Duke University, North Carolina, USA and sucessfully submitted for the award of Master of Philosophy to the Dublin Institute of Technology, 2010.

Abstract

Breast cancer is a malignancy of the epithelial cells comprising the mammary gland. As the ER is necessary for the growth of pproximately 70% of breast cancers, pharmaceutical efforts have focused on uncovering modulators of the ERα such as antiestrogens and Selective Oestrogen Receptor Modulator (SERMs). SERMs differ from pure ER antagonists in their capacity to display tissue-selective and C promoter dependent agonist-antagonist activities. Tamoxifen (TAM) is a SERM that is used in the treatment of hormonally responsive breast cancer. TAM is the most commonly used treatment for patients with ERα positive breast cancer. In this study we examined the role of Oestrogen Receptor (ER) signaling in the regulation of tissue Transglutaminase 2 gene (TGM2). TGM2 encodes tissue Transglutaminase (TG2), a multifunctional enzyme with many cellular functions, such as matrix remodelling, stabilization of apoptotic cells and cell adhesion and migration which are thought to be implicated in inhibition of tumour growth and prevention of metastasis. Ligand activated ER has been shown to induce the transcription of the TGM2. Our results show mRNA expression of TGM2 by E2/ER in breast cancer cells is maintained in the presence of TAM but not the SERM Raloxifene. As we would expect this gene to be inhibited by TAM, this reveals an added layer of complexity to the pharmacology of TAM. To investigate this finding further we studied the effects of compounds which are structurally related to TAM, and found that compounds such as Endoxifen and 4-Hydroxytamoxifen have similar effects to TAM. To analyse the sequence requirements for ER induced activation of TGM2 transcription we cloned the 5‟ regulatory region into a luciferase vector. Further study is required in this area to better understand the significance of TGM2 expression in breast cancer cells.

DOI

10.21427/D7RP66

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