Estrogen receptor (ER) positive breast cancer constitutes 75% of all breast cancer cases and the ER protein works closely with a pioneer factor called FOXA1 to bind to the genome. Both mutational data and experimental screening data have revealed potential candidates that influence ER/FOXA1 to contribute to ER+ cancer metastasis. Our global CRISPR screens have revealed a role for the transcription factor MAFG in ER+ metastasis. MAFG is a frequently amplified event in ER+ metastasis (10% of all metastases) and we have explored the functional consequences of elevated MAFG. We find that MAFG causes substantial changes in ER activity, resulting in the induction of genes that promote metastasis in the intraductal mouse model.
To directly assess the role of FOXA1 in metastasis, we have conducted FOXA1 RIME (IP-Mass Spec) from metastatic samples, to discover novel FOXA1-associated protein complexes and we have taken two orthogonal approaches. The first involves implanting ER+ breast cancer cells intraductally into mice, then enriching for a lung metastasis that has a preference for re-colonising the lung. FOXA1 RIME was conducted on matched primary tumours or lung-homing metastases, and we have explored the changes in protein interactions from this metastatic model. We also conducted FOXA1 RIME from a number of ER+ patient breast cancer samples or distant metastases that have arisen from ER+ breast cancers, including metastases in the lung, liver and abdomen. Identification of FOXA1 associated protein changes revealed the exact same differential protein interactions. We are currently exploring the functional relevance of these protein interactions.