Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn

RCSI Scientists in discovery of estrogen actions in colorectal cancer

25 September 2017

RCSI Scientists in discovery of estrogen actions in colorectal cancer

The female hormone estrogen is frequently considered to play a protective role in colorectal cancer (CRC). This is evidenced by epidemiological studies in premenopausal women, or postmenopausal women taking hormone replacement therapy, who are significantly less likely than males to develop CRC. Moreover, a better CRC survival of women compared to men is found especially in the younger age groups. This suggests a protective role for estrogen in CRC development. However, the role of estrogen and estrogen receptors in the onset and progression of CRC is not well understood. The RCSI team of scientists led by Prof Brian Harvey discovered that estrogen has opposite effects on the tumorgenicity of CRC depending on the degree of oxygen levels in the microenvironment of the cancer cells. The findings were published this month in Oncotarget, one of the highest impact journals in cancer research. The research team discovered that estrogen had a protective effect against CRC progression under normal oxygen levels in the tissue but the hormone stimulated the potential of the cancer cells to proliferate when exposed to hypoxia (low oxygen tensions as seen in the centre of a tumour or in advanced stage CRC). The team worked out the molecular mechanisms for the  protective and aggravating effects of estrogen and found these to be mediated by a novel estrogen receptor GPER which activated protective genes in normoxia and switched on cancer proliferation genes in hypoxia.

This study presents the first analysis of combined estrogen and hypoxia-mediated effects in CRC and identifies the mechanisms for protective effects of the hormone during the early stages of cancer development and a pro-tumorigenic role for estrogen as the tumour progresses in advanced disease.

The potential clinical relevance of GPER was analysed in tumours from 566 CRC patients based on patient gender and tumor stage at diagnosis. The researchers found that high expression of GPER was significantly associated with poor survival in women with stages 3 and 4 CRC, whereas, male patients showed no survival difference based on GPER expression. This patient data indicates a sexual dimorphism for a GPER role in CRC progression and survival and is consistent with the demonstration of a pro-tumorigenic role for estrogen, acting via GPER, under a hypoxic microenvironment in the tumour.


The full paper can be accessed online at