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Title: Oestrogen receptors in oesophageal cancer
Author: De Rosa, Antonella
ISNI:       0000 0004 7430 375X
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2018
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Introduction: Oesophageal cancer is more common in men than women. Oestrogen, which mediates its effects via oestrogen receptors (ERs), may be responsible for the gender disparity. This thesis investigates the role of ERs in oesophageal cancer development and explores potential therapeutic possibilities. Methods: ERα and ERβ expression in oesophageal AC cell lines (OE19 and OE33) was knocked down using siRNA, and the effect of knockdown on the expression of proliferation-associated proteins (Ki67, PCNA, E-cadherin, Cyclin D) was assessed. The effect of the SERM, tamoxifen, on oesophageal cancer cell proliferation was investigated using proliferation assays and by evaluating the effect of tamoxifen on proliferation-associated proteins. Finally, a pilot study of tamoxifen in patients with oesophageal cancer was undertaken to assess feasibility of a clinical trial and to determine the short-term biological effect of tamoxifen on proliferation, assessed by a change in the immunohistochemical expression of Ki67 between paired biopsies. Results: ERα and ERβ are expressed at the mRNA (RT-PCR) and protein level (Western Blotting) in the OE19 and OE33 cell lines. ERβ mRNA knock down was achieved in the OE33 cell line (p = < 0.0001). However, reproducible significant ERβ protein knockdown was not demonstrated, and there was no change in the expression of proliferation-associated proteins. Treatment with tamoxifen significantly inhibited OE33 cell proliferation in a dose-dependent manner (p = < 0.0001). Interestingly, treatment with tamoxifen decreased the expression of E-cadherin, but failed to change the expression of the remaining proliferation-associated proteins. Eight patients (6 male with AC and 2 female with SCC) included in the pilot study completed a median on 30 days (range: 28 – 45 days) tamoxifen treatment; the mean Ki67 Labelling Index between paired biopsies increased by 0.625% (ns). Of the two women included, Ki67 expression decreased with tamoxifen treatment. A correlation was demonstrated between a reduction in Ki67 and mean ERβ expression (r= -0.2272, ns). Discussion: ERβ is the dominant ER subtype expressed in oesophageal cancer cell lines and human cancer tissue. Tamoxifen inhibits the proliferation of oesophageal cancer cell lines in-vitro. Further studies to define the role of the ERβ subtype in oesophageal cancer and a clinical trial of tamoxifen in patients with oesophageal cancer is needed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: WI Digestive system