1. ¹EPHE INSERM 517, Faculty of Medicine, University of Bourgogne, Dijon, France
2. ²Department of Pathology, Centre G-F Leclerc, Dijon, France
3. ³Department of Biochemistry, University of Cambridge, Cambridge, UK

Correspondence: Dr A Pance, MSc, PhD, Department of Biochemistry, Hopkins Building, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK. E-mail: a.pance@bioc.cam.ac.uk

Received 29 November 2004; Revised 24 January 2005; Accepted 25 January 2005; Published online 21 March 2005.

Abstract

The presence of hormone receptors is related to survival outcome in breast cancer. Previous results from our laboratory established a correlation between the presence of nitric oxide synthase II (NOSII) and nitric oxide (NO) production with progesterone receptors in a series of human breast tumours. Furthermore, this was directly related to a lower tumour grade and a lower proliferation rate of the tumour cells. To examine these results in further detail, the effect of progesterone (Pg) and 17-oestradiol (E2) on NOSII expression was analysed in the human breast cancer cell line MCF-7. By Northern blot and promoter activity, we show that a cytokine mix (TNF-, IL-, and IFN-) induces NOSII transcription after 6 h stimulation. In the absence of cytokines, neither hormone affects NOSII expression. However, Pg but not E2, enhances cytokine-induced NOSII transcription as well as NO synthesis, mainly by cooperation with gamma-interferon. The increase in NO accumulation in the media induced by addition of Pg to the cytokine treatment significantly increases cell death, mainly accounted for by apoptosis, as compared to the effect of cytokines alone. Our findings help clarify the role of steroid hormones in NOSII expression as well as the effect on cell viability and may suggest novel approaches towards hormonotherapy and the treatment of cancer.