Oestrogen metabolism in colorectal cancer

Gilligan, Lorna Catherine (2017). Oestrogen metabolism in colorectal cancer. University of Birmingham. Ph.D.

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Abstract

Colorectal cancer (CRC) is the second most prevalent cancer. Although not typically considered a hormonally responsive malignancy, oestrogens are linked to disease risk and survival. Here, it is hypothesised that oestrogen synthesis, via steroid sulphatase (STS) and 17β-hydroxysteroid dehydrogenases (HSD17β), is promoted in CRC leading to oestrogen-driven tumour proliferation. To identify potential novel treatment targets oestrogen metabolism was characterised in CRC. Oestrogen metabolism was characterised in CRC cell lines and human colon tissue using Western blotting, qRT-PCR, STS activity assay and proliferation assays. A mass spectrometry method to quantify oestrogen metabolites was developed and validated for cell culture medium.

CRC exhibited increased STS activity indicating increased intratumoural oestrogen availability. In CRC a drive towards potent oestradiol production through decreased HSD17β2 expression (oxidative enzyme) and increased HSD17β7 and 12 expression (reductive enzymes) was seen. STS over-expression increased proliferation in CRC cell line HCT116, which was at least in part mediated through G protein-coupled oestrogen receptor action. Additionally, STS activity was regulated in vitro and in vivo by the inflammatory modulator TNFα.

This thesis demonstrates that increased STS activity and oestrogen synthesis in CRC increases tumour proliferation via GPER. Thus, multiple novel targets have been identified to impede CRC proliferation.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):