A transcriptional analysis of sirtuins in breast cancer

Ashraf, Nadeem (2007) A transcriptional analysis of sirtuins in breast cancer. MD thesis, University of Glasgow.

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Abstract

Breast cancer is the most common cancer to affect women, and is associated with abnormalities in normal growth and proliferation. An alternative way for understanding this disease, is to view it as an aberration of normal biological ageing. The mitochondrion, telomere nucleo-protein complex and ribosomal DNA, comprise the MTR, and link energy production, protein synthesis and DNA damage responses. Sirtuins act within the various components of the MTR, imbalance of which, may result in accelerated ageing, disease and tumorogenesis, a hypothesis first described by Shiels and Davies (2003). Consistent with this viewpoint, altered sirtuin expression is associated with a number of ageing-related diseases, progeroid conditions and malignancies. This observation makes their study particularly pertinent for understanding how breast cancer develops and progresses from a platform of aberrant biological ageing. Similarly, the study of sirtuins may be relevant to the study of breast cancer therapy, as these treatments induce cellular senescence and apoptosis, abnormalities of which are also implicated in ageing. Furthermore, the ability of breast cancer cells to withstand the insult of cytotoxic treatments may be determined by the biological age of tumour cells. The aim of the research presented within this thesis, was to study breast cancer as an aberration of normal biological ageing, with respect to sirtuin expression. It specifically sought to determine whether there was an association between the transcriptional expression of sirtuins and breast cancer pathogenesis and treatment. The transcriptional expression of sirtuins was initially investigated in primary and immortalised mammary epithelial cells, as a function of in vitro growth. In order to determine whether changes in biological ageing, observed in primary mammary epithelial cells, were pertinent to breast cancer in vivo, transcriptional expression of sirtuins was studied in non-malignant and malignant breast tissue biopsies. Transcriptional studies were also performed to determine the relationship between common therapies used for the treatment of breast cancer, namely radiotherapy and chemotherapy, and sirtuin expression. Specifically, sirtuin expression was investigated in breast cancer cells in response to cellular irradiation and paclitaxel treatment. The expression of SIRT3 and SIRT7, the gene products of which act at the mitochondrion and ribosomal DNA components of the MTR, was found to increase as cells underwent replicative ageing. Similarly, the transcriptional expression of SIRT3 and SIRT7 was elevated in lymph node positive breast cancer biopsies compared to non-malignant breast biopsies. In contrast, SIRTl and SIRT2 showed no difference in expression in either replicatively ageing cells or between malignant and non- malignant breast biopsies. The increased SIRT3 and SIRT7 expression observed in lymph node positive breast cancer biopsies, suggests that tumours associated with more invasive disease display perturbation within components of the MTR, indicative of increased biological ageing. In breast cancer cells exposed to irradiation and paclitaxel treatment, SIRT2 and SIRT7 transcriptional expression was found to increase. In contrast, SIRTl and SIRT3 expression remained relatively unchanged. The increased expression of SIRT2 and SIRT7 in response to these treatments, suggests that these therapies target components of the MTR that are associated with mitotic growth arrest. In particular, SIRT7, is associated with ageing and indicates that these agents induce ageing in these tumour cells. In summary, this research shows aberrant sirtuin expression to be a feature of primary mammary epithelial cell senescence, breast cancer pathogenesis and damage responses in breast cancer cells, secondary to ionizing radiation and paclitaxel therapy.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Paul Shiels
Keywords: Oncology
Date of Award: 2007
Depositing User: Enlighten Team
Unique ID: glathesis:2007-71131
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 10 May 2019 10:49
URI: http://theses.gla.ac.uk/id/eprint/71131

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