Breast cancer is one of the most common cancers in the world, and the second leading cause of cancer-related deaths in women. In more than 70% of breast cancer patients, the estrogen receptor α (ERα) plays a major role in disease progression and significant research efforts to date have focused on this oncogenic transcription factor. Tamoxifen is the standard-of-care first-line agent for ERα-positive breast cancer patients, yet frustratingly, many patients will eventually develop drug resistance and metastatic disease during their treatment.
Davide Ruggero and his group recently made an unexpected discovery: that ERα has a unique RNA-binding domain allowing it to interact directly with RNA in the cytoplasm of cells. This new role for ERα may be a game changer, as it was previously only known to bind DNA in the nucleus as a typical transcription factor. Ruggero has identified over 1000 mRNAs that are associated with ERα, and his preliminary data suggest that ERα may regulate the translation of its target mRNAs. His team has also generated a novel cell line that specifically impairs the RNA-binding activity of ERα without affecting its classical transcription function, and shown that this leads to reduced tumor growth in xenograft mouse models.
Here, the team will investigate genome-wide changes in translation efficiency, which may uncover how ERα’s RNA-binding activity influences gene expression in breast cancer development. They will also dissect the role of this RNA-binding activity in vivo in tumors, cancer progression and metastases. Finally, they will interrogate the therapeutic potential of existing clinical translation inhibitors. The outcomes of this ASPIRE Award will increase our understanding of post-transcriptional networks in cancer, and give rise to potentially new biomarkers and innovative therapeutic strategies.