ERa is a novel RNA-binding protein controlling breast cancer

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ERα is a novel RNA-binding protein controlling breast cancer Breast cancer is one of the most common cancers in the world, with over 70% of breast cancers harboring the activation of the estrogen receptor α (ERα), a key oncogenic transcription factor. Almost all research on the function of ERα in breast cancer has been predominantly centered on the role of ERα as a transcription factor. We have instead made a striking discovery that ERα is an RNA-binding protein (RBP) with an ascribed RNA- binding domain (RBD). We performed high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) and CRISPR analyses to unravel a unique network of mRNAs, crucial for cancer progression. Notably, we further discovered that mutating the ERα RBD, without affecting its DNA-binding activity, significantly impedes breast cancer cell growth both in vitro and in vivo. Importantly, the percentage of ERα binding to mRNA is significantly increased in cells resistant to tamoxifen, an antagonist targeting the transcriptional activity of ERα. Mutation of the RBD in ERα or inhibition of targets of ERα such as the antiapoptotic protein MCL1 re-sensitize resistant breast cancer cells to tamoxifen-induced cell cycle arrest and cell death. Based on these results, we hypothesize that ERα is a previously uncharacterized RBP that modulates post- transcriptional gene expression to sustain breast cancer progression and therapy resistance. These findings transform our understanding of ERα and the molecular underpinnings of breast cancer. In this grant, we leverage our compelling preliminary results to define the mechanisms by which ERα reprograms gene expression at the post-transcription level as a means to contribute to tumor progression and drug resistance. Specifically, in Aim 1, we will harness the power of two state-of-the-art technologies to define the mechanisms by which ERα regulates post-transcriptional gene expression in breast cancer at the level of mRNA stability and translation control. In Aim 2, we will delineate the mechanisms by which ERα-mediated RNA metabolism stimulates the Integrated stress response (ISR) and Unfolded Protein Response (UPR), which are adaptive pathways critical for cancer development. We will also characterize the role of eIF2-eIF2B in ERα-mediated post-transcriptional regulation in cancer development and progression in vivo. In Aim 3, we will characterize the role of ERα as an RBP in breast cancer and its therapeutic implications. We will employ elegant genetic mouse models as well as xenografts and orthotopic models to dissect the role of ERα RNA-binding activity in-vivo. Therefore, we will be in a strong position to unveil the function of ERα RNA-binding activity on tumor initiation, progression, metastasis formation, and therapeutic response.