Oral Presentation Joint 2016 COSA and ANZBCTG Annual Scientific Meeting

Breast cancer and metastasis: New insights into cell death pathways (#104)

Delphine Merino 1
  1. Walter and Eliza Hall of Medical Research, Parkville, VIC, Australia

Metastasis spread is a multiple step process, and cell death is a major obstacle for a potential metastatic cell. Whereas large numbers of cells from a primary tumour may gain access to the circulation, few of them will give rise to metastases. The mechanism of elimination of these tumour cells, often termed “metastatic inefficiency” is poorly understood. It is known that the overexpression of anti-apoptotic proteins of the BCL-2 family plays a key role in the pathogenesis of many solid tumours. Studies of various cancers have reported a link between BCL-2 family members and outcomes for patients. It will be important to determine which of these proteins may be involved in the survival of metastasis.

Using the transgenic PyMT model and metaplastic human tumours, we recently reported that the pro-apoptotic protein BIM is upregulated at the tumour border, and act as a metastasis suppressor in breast cancer (Merino, Best et al., Oncogene 2015). The relevance of this finding in human disease, and the identification of other cell death mediators in this process will require more work using patient derived xenografts (PDX). Our laboratory generated an extensive bank of breast tumour xenografts that include ER-positive, HER2-positive, and triple negative tumours, which lack ER, progesterone receptor (PR), and HER2 expression. We have previously shown that these PDXs recapitulate features of primary tumours, and can be used as pre-clinical models to evaluate the efficacy of new drug combinations including chemotherapy, endocrine therapy and BH3 mimetics (Vaillant, Merino et al., Cancer Cell 2013). More recently, we characterized the ability of these PDXs to metastasize in NSG mice, and perform RNAseq analysis in circulating tumour cells (Unpublished). These models are useful not only to understand how bread cancer spreads, but also to favour the development of treatment for advanced disease.