Defining mechanisms of hormone-dependent cancer disease progression

Background: Hormone-dependent cancers constitute two of the most common cancer types (ER+ breast and prostate cancer).

Treatments that block the driving transcription factors, ER in breast and AR in prostate, have improved survival rates substantially, but treatment resistance is a common clinical problem.

The core cell-type defining transcription factors have been identified in primary disease and include pioneer factors such as FOXA1 and a number of co-regulatory proteins and associated transcription factors. Recently, proteomic and genetic screens have linked numerous additional factors with these transcriptional complexes.

Aims: The central aim is to define the biological processes and the critical changes that contribute to endocrine-resistant, metastatic disease.

This will involve the discovery of genes and proteins involved in breast cancer metastasis, the identification of the role of key pioneer factors in this process and analysis of the role of specific mutations in treatment response and metastasis. We will also explore a hypothesis around the role of FOXA1 in prostate cancer progression.

Methods: The proposal builds on a wealth of background information and novel methodological tools, to enable an unbiased and global investigation of the key events that contribute to ER/FOXA1 transcriptional activity in breast cancer and AR/FOXA1 transcriptional activity in prostate cancer.

The work will identify key genes and associated proteins that influence tumour progression, it will explore the functional interaction and dynamics between known, but uncharacterised co-regulatory proteins, it will exploit global CRISPR screens and a method we developed called qPLEX-RIME, which permits unbiased discovery of protein interactomes from clinical samples.

In addition, the work will exploit a contemporary and clinically relevant in vivo model of luminal breast cancer metastasis.

As a community, we have been studying primary breast for decades, but our understanding of the events that drive metastasis are poorly understood.

This is in large part because we have been unable to accurately and faithfully model luminal (ER+) breast cancer metastasis and there has been limited access to metastatic samples.

The advent of the intraductal tumour engraftment (MIND) system, provides the first reliable and physiologically relevant approach for studying ER+ breast cancer metastasis.

How the results will be used: The measurable endpoints of this proposal will be the identification of the critical components in the transcriptional complex, an understanding of the events that drive metastasis, clarity around the impact of specific mutational events on this process and new insight into potential ways of therapeutically intervening in these contexts.