Author: Steven L Due
Due, Steven L, 2018 The Oestrogen Receptor: A Novel Therapeutic Target in Oesophageal Adenocarcinoma, Flinders University, College of Medicine and Public Health
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Oesophageal adenocarcinoma is a highly lethal malignancy that is increasing in incidence at an alarming rate. Many patients receive chemotherapy as part of their treatment strategy. Targeted molecular therapies are emerging as valuable adjuvant therapies in many types of cancer, but advances in oesophageal adenocarcinoma are lacking.
Emerging evidence demonstrates that oestrogen receptors (ERs) regulate cell growth and cell death in a variety of normal and abnormal human tissue types, including cancers of epithelial origin. This is mediated by the two major ER subtypes, ERα and ERβ, which influence cell growth directly and have indirect activity by interactions with other well-known cell growth pathways. ERs have been detected in oesophageal adenocarcinoma tissues and may therefore represent a therapeutic target.
In this thesis, cancer cell growth and survival were modulated in oesophageal adenocarcinoma cells by treating them with drugs that interact with ERs. Both major ER subtypes, ERα and ERβ, were detected in patient-derived oesophageal adenocarcinoma tissues and cell culture models. The key metabolites of the ER modulator tamoxifen were found to be both cytostatic (slowing cancer growth) and cytotoxic (inducing cancer cell death) in this malignancy. The magnitude of effect was comparable to breast cancer cells treated in identical model systems, suggesting clinical potential. This potential appeared to be mediated by various isoforms of ERα and ERβ, and by interactions with related pathways such as those belonging to the epidermal growth factor receptor (EGFR) family, and the tumour suppressor molecule p53. Such interactions were found to mirror those described in the breast cancer literature, supporting the notion that ER networks may be a legitimate therapeutic target in oesophageal adenocarcinoma. Additionally, there was a favourable interaction between tamoxifen metabolites and conventional chemotherapy agents which implies that tamoxifen could be administered concurrently with existing regimens. In the final series of experiments, fresh endoscopic biopsies of oesophageal adenocarcinoma tumours were cultured ex vivo in the laboratory. Treatment of these explants with the major metabolites of tamoxifen appeared to induce cell death, though these experiments were limited by the small number of explants that reached the experimental end point.
Together, the findings presented in this thesis indicate that ERα and ERβ are expressed in oesophageal adenocarcinoma and appear to influence cell growth and survival. Cell culture models suggest that cancer growth can be regulated by metabolites of the ER modulator tamoxifen. Mechanistic similarities to breast cancer cells treated in identical model systems raises the possibility of future clinical translation. Small-scale investigation in another pre-clinical explant model supports this assertion. Since oesophageal adenocarcinoma is an aggressive malignancy that usually requires chemotherapy, and given that ER modulators are safe, inexpensive, and widely available, the evaluation of these agents in a clinical context may be worthwhile.
Keywords: Oesophageal cancer, targeted therapies, oestrogen receptors, adjuvant therapies, selective oestrogen receptor modulators, tamoxifen
Subject: Biological Sciences thesis, Medical Science thesis
Thesis type: Doctor of Philosophy
Completed: 2018
School: College of Medicine and Public Health
Supervisor: Dr Damian Hussey