Heregulin (Neuregulin)/HER3 signalling increases invasive behaviour of HER2-positive breast cancer cells

Abstract

Breast cancer is a heterogeneous disease with distinct histological and molecular subtypes differing in prognosis, response to therapy and metastatic behaviour. Like most cancers, poor outcome in breast cancer is related to tumour cell spread and colonisation of distant organs, which ultimately disrupts local and systemic physiological processes to the demise of the patient. Colonisation of the brain is arguably the most aggressive manifestation of metastatic disease. Brain metastasis is a growing public health problem associated with a high degree of morbidity and virtually 100% mortality. The current treatments for these patients are surgery, radiotherapy and chemotherapy, but their outcome remains poor. In this regard, the management of brain metastases is an unmet medical need for which establishment of more effective preventive and therapeutic treatment strategies is of paramount importance. In order to achieve that, we need to deepen our knowledge and insights about the molecular mechanisms and signal transduction pathways underlying initiation and progression of brain metastases.Invasion of breast tumour cells across the basement membrane and endothelium to gain entry to the blood stream and lymphovascular system is a critical early requirement for metastasis.Disseminated cells must then undergo extravasation at distant tissue sites. In the case of brain metastases, cells must breach the highly specialised and impermeable blood-brain-barrier.Improving our understanding of the molecular mechanisms underlying these processes may reveal new drug targets to prevent development or suppress growth of these lethal tumours.Of all the breast cancer subtypes, patients with HER2-positive disease (amplification and/or overexpression of the ERBB2 receptor tyrosine kinase) exhibit the highest frequency of brain metastases. Both HER2 and its obligate dimerisation partner, HER3 (ERBB3), are associated with development of brain metastases, though a mechanistic link has not yet been established.The main goal of this project was to elucidate the molecular mechanisms by which the HER2/HER3 heterodimer promotes metastatic progression and more specifically, development of brain metastases. In order to achieve this, activation of the HER2/HER3 iv