Oestrogen receptor alpha (
ERalpha) is an oestrogen-activated
transcription factor, which regulates proliferation and differentiation of mammary epithelial cells by activating or repressing gene expression.
ERalpha is a critical prognostic
indicator and a therapeutic target for
breast cancer. Patients with tumours that express higher level of
ERalpha have better prognosis than patients with tumours that are
ERalpha negative or express lower level of
ERalpha. Better prognosis in
ERalpha-positive patients is believed to be due to repression of proinvasive gene expression by
ERalpha. Oestrogen receptor alpha represses gene expression by transrepressing the activity of the
transcription factors such as
nuclear factor-kappaB or by inducing the expression of transcriptional suppressors such as MTA3. In this report, we show that
ERalpha transrepresses the expression of the proinvasive gene
interleukin 6 (IL-6) in
ERalpha-negative MDA-MB-231
breast cancer cells stably overexpressing
ERalpha. Using these cells as well as
ERalpha-positive MCF-7 and ZR-75-1 cells, we show that tumour
necrosis factor alpha (
TNFalpha) and the phosphatidylinositol-3-kinase (PI3-kinase) modulate transrepression function of
ERalpha by reducing its stability. From these results, we propose that
TNFalpha expression or
PI3-kinase activation lead to reduced levels of
ERalpha protein in
cancer cells and corresponding loss of transrepression function and acquisition of an invasive phenotype.