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¹ Department of Internal Medicine, School of Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
² Department of Clinical Physiopathology, School of Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
³ Department of Pediatrics School of Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
⁴ DEGENE Spin off, School of Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy

(Requests for offprints should be addressed to M L Brandi; Email: m.brandi{at}dmi.unifi.it)

Several strands of evidence indicate that oestrogens exert a protective role against the development of colon cancer through indirect and direct effects on colonic epithelium. Oestrogen receptor ß (ERß), the predominant ER subtype in human colon, is significantly decreased in colonic tumours compared with normal mucosa suggesting a potential role in the regulation of colon tumour growth.

To investigate this hypothesis we engineered human colon cancer ER-negative HCT8 cells in order to obtain ERß protein over-expression. Stably transfected cells were cloned and ERß expression and functionality were monitored by RT-PCR, Western blotting and transactivation in an assay using oestrogen-responsive reporter constructs.

Over-expression of ERß inhibited cell proliferation and increased cell adhesion in a ligand-independent manner. Its constitutive activation is possibly due to cross-talk with intracellular signalling pathways, as epidermal growth factor and IGF-I were able to induce ERß transactivation.

A possible mechanism by which ERß over-expression inhibits proliferation in HCT8 cells is by modulation of some key regulators of the cell cycle; there is a decrease in cyclin E and an increase in the cdk inhibitor p21CIP1. In fact, flow cytometry analysis provided evidence for blocking of the G1-S phase progression induced by ERß over-expression. The magnitude of this effect was affected by the level of ERß expression.

These results provide the first direct evidence that ERß plays an important role in colon cancer as a regulator of cell proliferation through the control of key cell cycle modulators and arrest in G1-S phase transition. These findings are compatible with the hypothesis that the loss of ERß expression could be one of the events involved in the development or progression of colon cancer.

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