Understanding breast cancer's multiple variants

TNew findings presented at Europe's leading breast cancer translational research conference this year shed new light on the many biological differences between individual breast cancers. Focussed on the biological features that make tumours more or less sensitive to important therapies, the new studies will help doctors make crucial choices about the most appropriate treatment for millions of patients. "Despite major advances in the treatment of breast cancer many patients continue to relapse and die from the disease," noted Prof Mitch Dowsett from the Royal Marsden Hospital, UK, former IMPAKT Chair. "Studies presented at this year's IMPAKT further emphasise the potential of biomarkers to identify new targets for developing therapy to disease that is resistant to our current treatments as well as the groups of patients most likely to respond to the new treatments. In this way we are progressively reducing the threat posed by a diagnosis of breast cancer and doing this in a personalised fashion." A possible mechanism for endocrine resistance An experimental model of breast cancer has yielded exciting new insights into why some breast cancers become resistant to endocrine therapies such as tamoxifen, say researchers from the US and Italy. Their findings could lead to new treatments and prognostic tests for the disease. "Endocrine resistance in breast cancer is a major clinical issue. Despite years of studies, we still have an incomplete view of the molecular mechanisms that determine endocrine resistance and this limits the potential for developing new therapeutics," explained Dr Luca Malorni, from the Hospital of Prato, Italy and the Breast Center at Baylor College of Medicine, Houston-TX. Previous observations from his group and others suggested that the transcription factor AP-1 might play a relevant role in endocrine resistance. AP-1 is known to regulate gene expression in response to a variety of stimuli. To clarify this issue, they used a genetic mechanism to block the AP-1 pathway in mice and cell culture. The researchers report that inhibiting AP-1 enhanced the effects of tamoxifen and delayed the development of tamoxifen resistance. Their data suggest that specific drugs with 'AP-1 inhibitory' effects might be useful in combination with available endocrine agents to develop new, more efficacious treatments. "Fully understanding the biology behind endocrine resistance is the first step to design new drugs. I think that our data represent such a step forward," Dr Malorni said. "At the same time, our data might be helpful in deriving new biomarkers that could identify patients at higher risk of developing endocrine resistance. This might be an important contribution as today we are able to only partially predict response to endocrine treatment with the available biomarkers." The researchers propose that endocrine resistance develops when the estrogen receptor 'switches' from its classical direct binding to specific oestrogen responsive elements in the tumour genome, to an indirect DNA binding program via AP-1.