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dc.contributor.advisorDunbier, Anita
dc.contributor.authorBundock, Anna Sophia
dc.date.available2016-09-14T20:47:56Z
dc.date.copyright2016
dc.identifier.citationBundock, A. S. (2016). The effect of Tamoxifen and Fulvestrant on pro-inflammatory markers in oestrogen receptor positive breast cancer (Thesis, Master of Science). University of Otago. Retrieved from http://hdl.handle.net/10523/6778en
dc.identifier.urihttp://hdl.handle.net/10523/6778
dc.description.abstractOestrogen receptor α (ERα) positive breast cancer is the most prevalent form of breast cancer diagnosed. While a number of therapeutics have been developed targeting the dependence of these cancers on oestrogen for the transcription of genes related to cell growth and proliferation, a significant problem in the treatment of ERα+ breast cancers is the development of oestrogen independent growth. An association between poor antiproliferative response to aromatase inhibitors and an increased level of lymphocytic infiltration in ERα+ cancer has led to the suggestion that the interaction of neoplastic and immune cells facilitates the development of a pro-tumour microenvironment which supports cell growth and proliferation in the absence of oestrogen. This notion is supported by previous work, which has shown that three pro-inflammatory chemokine encoding genes, CCL5, CCL22 and CXCL16, were upregulated in oestrogen deprived MCF-7 cells. This project aimed to determine whether the expression of these three pro-inflammatory chemokines is modulated in response to treatment with two other classes of anti-oestrogen therapies; Tamoxifen and Fulvestrant, in two ER+ cell lines. In response to Tamoxifen treatment, MCF-7 and T47D cells expressed the three chemokines in markedly different patterns. CCL5 and CXCL16 expression were not modulated in response to Tamoxifen in MCF-7 cells, but were significantly down and upregulated in T47D respectively. The expression of CCL22 was greater in treated MCF-7 cells compared to controls, while down regulated in Tamoxifen treated T47D cells. In response to Fulvestrant treatment, CCL5 and CCL22 were found to be upregulated in MCF-7 cells, while CCL22 alone was modulated in T47D cells. To further examine the effect of upregulated pro-inflammatory chemokines following Tamoxifen and Fulvestrant treatment, we examined the number of immune cells which had transmigrated in response to a chemotactic gradient towards treated MCF-7 cells. Significantly more immune cells migrated towards Fulvestrant treated cells compared to the control, however no significant difference in migration was observed towards Tamoxifen treated cells or the control. Additionally, we examined the expression of CCL5, CCL22 and CXCL16 in vivo, in response to the aromatase inhibitor, Letrozole or Letrozole and Celecoxib in combination. This was achieved using STAT1-/- tumours in immunocompetent mice, which model ERα+ breast cancer. We found no significant difference in the expression of the chemokines of interests between treatments or the controls. We also examined microarray data from ER+ breast cancers from post-menopausal women treated with 250mg/28 days or 500mg (on day 0,14, 278 and monthly thereafter) of Fulvestrant, and found five and 19 unique chemokine and chemokine receptors respectively, which were regulated by treatment. From our three chemokines of interest, CCL5 alone was found to be up-regulated in patients treated with 500mg of Fulvestrant. No significant alteration in expression of these chemokines was observed patients treated with 250mg. We suggest that the expression of pro-inflammatory chemokines is regulated in response to anti-oestrogen therapy in both a cell line and treatment specific manner. This study has highlighted the importance of considering the interactions between cancer cells, the immune response and the tumour microenvironment when examining the response of cancer to therapeutics.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectTamoxifen
dc.subjectFulvestrant
dc.subjectOestrogen receptor
dc.subjectBreast cancer
dc.subjectPro-inflammatory
dc.subjectChemokines
dc.subjectImmune
dc.subjectOestrogen independent growth
dc.subjectResistance
dc.subjectPro-tumour microenvironment
dc.subjectCCL5
dc.subjectCCL22
dc.subjectCXCL16
dc.subjectOestrogen deprived
dc.subjectMCF-7
dc.subjectT47D
dc.subjectanti-oestrogen therapy
dc.subjectaromatase inhibitor
dc.subjectin vitro
dc.subjectin vivo
dc.subjectLetrozole
dc.subjectCelecoxib
dc.subjectSTAT1-/-
dc.titleThe effect of Tamoxifen and Fulvestrant on pro-inflammatory markers in oestrogen receptor positive breast cancer
dc.typeThesis
dc.date.updated2016-09-14T10:04:49Z
dc.language.rfc3066en
thesis.degree.disciplineGenetics
thesis.degree.nameMaster of Science
thesis.degree.grantorUniversity of Otago
thesis.degree.levelMasters
otago.openaccessOpen
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