Therapeutics

Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor. Wang, L. H. et al. Nature Med. 14 Dec 2003 (doi:10.1038/nm969)

Breast cancer therapies that involve blocking ligand binding to the oestrogen receptor (ER) are limited, as the drugs used can activate the ER in some cancer cells. Wang et al. found that electrophilic agents that disrupt zinc fingers in the DNA-binding domain of the ER downregulate expression from oestrogen-responsive elements and inhibit the proliferation of breast tumour cells in a mouse xenograft model, indicating that these agents could be used as alternative treatments for ER-expressing breast cancers.

Tumour progression

Role of thymosin-β4 in tumor metastasis and angiogenesis. Cha, H. -J., Jeong, M. -J. & Kleinman, H. K. J. Natl Cancer Inst. 95, 1674–1680 (2003)

Thymosin-β4 expression is associated with increased metastatic potential in tumour cells, but the mechanisms underlying this are unclear. Cha et al. overexpressed thymosin-β4 in tumour cells and saw increases in the numbers of blood vessels associated with tumours, and increased cell migration and expression of vascular endothelial growth factor (VEGF). So, thymosin-β4 seems to promote tumour progression by stimulating angiogenesis — either directly or by increasing VEGF expression — and by promoting cell migration, which might be due to its actin-binding function.

Clinical trials

Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. Kurzrock, R. et al. Blood 102, 4527–4534 (2003)

Farnesylation is essential for the activity of several proteins, including the RAS oncoprotein. The farnesyltransferase inhibitor R115777 inhibits tumour growth in vitro and in animal models. Kurzrock et al. carried out Phase I clinical trials of R115777 in patients with myelodysplastic syndrome, a group of pro-leukaemic disorders in which RAS mutations are seen in ∼25% of cases. Responses to R115777 were seen in 30% of patients, although only one-third of these had RAS mutations.

Tumour suppressors

Arf tumor suppressor promoter monitors latent oncogenic signals in vivo. Zindy, F. et al. Proc. Natl Acad. Sci. USA 100, 15930–15935 (2003)

Activation of the tumour suppressor Arf is difficult to detect in vivo, probably because cells that express Arf die or undergo growth arrest. Zindy et al. made transgenic mice in which the Arf coding region was replaced by a green fluorescent protein (GFP) complementary DNA. They monitored GFP fluorescence to confirm that the Arf promoter is activated in response to a range of oncogenic signals.