IMPAKT News: AP-1 may be a new hallmark of resistance to endocrine therapy

AP-1 is critical in a switch in the estrogen receptor transcriptional programme

Latest findings presented at Europe’s leading breast cancer translational research conference shed new light on the many biological differences that make tumours more or less sensitive to important therapies. An experimental model of breast cancer has yielded exciting new insights into why some breast cancers become resistant to endocrine therapies such as tamoxifen. The 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, researchers still have an incomplete view of the molecular mechanisms that determine endocrine resistance and this limits the potential for developing new therapeutics reported Dr Luca Malorni from the Hospital of Prato, Italy and the Breast Centre at Baylor College of Medicine, Houston, USA at the 4th IMPAKT Breast Cancer Conference (3-5 May 2012), in Brussels, Belgium.

Previous observations from his group and others suggested that the transcription factor AP-1 might play a relevant role in endocrine resistance. It is known as a transcription factor downstream of different growth factor receptors and stress-related signalling cascades.

To clarify this issue, they used a genetic mechanism to block the AP-1 pathway in mice and cell culture. In these experiments, inhibiting AP-1 enhanced the effects of tamoxifen and delayed the development of tamoxifen resistance. These 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.

Understanding the biology behind endocrine resistance is the first step to design new drugs

Novel data from this work 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 it is possible to only partially predict response to endocrine treatment with the available biomarkers.
 
The researchers proposed that endocrine resistance develops when the oestrogen receptor switches from its classical direct binding to specific oestrogen responsive elements in the tumour genome, to an indirect DNA binding programme via AP-1. In this light, AP-1 cooperation with oestrogen receptor might be considered as a fundamental feature of the endocrine-resistant breast cancer cells. The researchers cannot exclude, however, that AP-1 activity independently of oestrogen receptor is also important. More studies are needed to dissect these different mechanisms.

The researchers hope that their data could stimulate researchers in this field to consider the switch in oestrogen receptor activity in their studies. For instance, common techniques to evaluate oestrogen receptor activity in vitro rely only on measurements of oestrogen receptor-related functions. The data from this study suggest that this might be an incomplete view that needs to be implemented with measurements of other oestrogen receptor functions as well, such as those that are related to AP-1.