Oral Presentation 27th Lorne Cancer Conference 2015

Breast cancer and metastasis: new insights into BCL-2 family members (#13)

Delphine Merino 1 2 , S Best 1 2 , F Vaillant 1 2 , JE Visvader 1 2 , GJ Linderman 1 2 3
  1. Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
  3. Department of Medical Oncology, Royal Melbourne Hospital, Melbourne, 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 tumor may gain access to the circulation, few of them will give rise to metastases. The mechanism of elimination of these tumor 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 tumors, we recently reported that the pro-apoptotic protein BIM is upregulated at the tumor border, and act as a metastasis suppressor in breast cancer1. Interestingly, whereas the deletion of BIM doesn’t affect the growth of the primary tumors, it significantly decreases the ability of tumor cells to survive in the lung microenvironment. The relevance of this finding in human disease, and the identification of BIM binding partners will require more work using patient derived xenografts (PDX).

Our laboratory generated an extensive bank of breast tumor xenografts that include ER-positive, HER2-positive, and triple negative tumors, which lack ER, progesterone receptor (PR), and HER2 expression. We have previously shown that these PDX recapitulate features of primary tumors, and can be used as pre-clinical models to evaluate the efficacy of new drug combinations including chemotherapy, endocrine therapy and BH3 mimetics2,3. More recently, we characterized the ability of these PDX to metastasize in NSG mice (Unpublished). These models will be useful not only to understand how bread cancer spreads, but will also help in the development of treatment for advanced disease.

1. Merino, D., Best, S., et al. (2014). "Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2." Oncogene, in press.

2. Oakes, S. R., Vaillant, F., et al. (2012). "Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737." Proc Natl Acad Sci U S A 109(8): 2766-2771.

3. Vaillant, F., Merino D., et al. (2013). "Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer." Cancer Cell 24(1): 120-129.