Drug Discovery Opinion

DDO Limited – Consultancy for Biotech and Pharma

Jun 03 2009

AT1 Receptor Linked to Subset of Breast Cancers

Posted by SR in News, tags: oncology, personalised medicine

pink bridge Increasingly, scientists and doctors are trying to personalise cancer treatment by identifying genetic alterations involved in the disease in individual patients. One example is the development of a monoclonal antibody, trastuzumab (Herceptin™), directed against the ErbB-2 (HER2) protein which is overexpressed in a subset of breast cancers and leads to a highly aggressive form of the disease.

DNA microarrays have been widely used to study gene expression in cancer and a team of US researchers have now used the technique to search for other genes that are overexpressed in breast cancers. Writing in the journal PNAS, the team describe a meta analysis of 31 breast cancer gene profiling studies comprising almost 3,200 microarrays. As well as correctly identifying the known breast cancer-associated gene, ErbB-2, the study found that the angiotensin II receptor type I (AT₁) was markedly overexpressed (up to 100-fold) in 10-20% of tumours across multiple independent cohorts. AT₁ overexpression was found only in oestrogen receptor (ER)-positive tumours and was also restricted to samples that did not overexpress ErbB-2. In primary mammary epithelial cells, ectopic overexpression of AT₁ together with angiotensin II stimulation led to a highly invasive phenotype that was attenuated by the AT₁ antagonist, losartan. In mice, treatment with losartan (90 mg/kg/day) for eight weeks was found to reduce tumour growth by 30% in AT₁-positive breast cancer xenografts.

AT₁ has previously been linked to cancer and cancer-related signalling pathways and the new study suggests that women with AT₁-overexpressing breast cancer may benefit from treatment with an AT₁ antagonist. Earlier studies have linked polymorphisms in the angiotensin pathway with breast cancer incidence and, although studies have not found a significant relationship between antihypertensive therapy and breast cancer incidence, the authors believe that the studies may not have been sufficiently powered to detect the small changes in incidence that might be expected from a subset of only 10-20% of AT₁-positive patients.

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