Oral Presentation 14th International Biennial Conference on Metastasis Research 2012

A functional in vivo shRNA screen for regulators of breast cancer metastasis (#48)

Richard P Redvers 1 , Kaylene J Simpson 1 , Izhak Haviv 1 , Robin L Anderson 1
  1. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

Approximately 1.5 million women worldwide are diagnosed with breast cancer annually, many of whom will have occult metastases at first diagnosis. Despite significant improvements in early diagnosis and treatment, these metastatic outgrowths will progress to life threatening lesions in about 20% of patients, for whom few cures exist. The molecular mechanisms underlying metastasis remain poorly understood but are known to include the loss of a class of genes termed metastasis suppressors. Thus far, only a handful of these critical determinants of breast cancer metastasis have been identified. We hypothesised that the loss of one of these genes in a poorly metastatic tumour line would lead to the genesis of a cell with significantly improved metastatic capabilities and the spread of such transmogrified variants to distant organs would provide sufficient selective pressure to enrich for those cells deficient in a specific bona fide metastasis suppressor transcript.

Using our clinically relevant model of spontaneous breast cancer metastasis, we initiated a genome-wide in vivo shRNA screen to identify genes involved in spontaneous dissemination of tumour cells to distant organs. Significantly, our preliminary screen yielded three candidates whose loss permitted metastasis to spine, namely Hsd17b13, an enzyme involved in steroid metabolism, Muc15, a cell surface glycoprotein known to suppress invasion of trophoblasts, and Pdlim1, one of the PDZ-LIM proteins involved in stabilising focal adhesions. Remarkably, all three are significantly diminished at the DNA and transcript levels in large human cohorts of aggressive breast carcinomas versus normal breast tissue (Oncomine). We are continuing our screen using a next-generation sequencing approach to rigorously evaluate candidates on a genome-wide basis and will validate these in our in vivo model.

It is of paramount importance that we identify functionally relevant metastasis suppressors and understand their biology to provide novel therapeutic opportunities for those with incurable disease.