Abstract 1996: Regulation of RNA splicing of the ErbB family receptors by the splicing cofactor SON

For women, breast cancer has the highest number of annual diagnoses and causes the second highest number of cancer related deaths per year. Receptor tyrosine kinases like those in the ErbB family play a crucial role in breast cancer progression by providing cancer cells proliferative and anti-apoptotic advantages. By targeting the ErbB family with monoclonal antibodies and kinase inhibitors, the prognosis of patients has improved dramatically, but resistance to these therapies does occur which requires novel therapies to be developed. One promising approach to circumvent drug resistance and inhibit tumor growth is to interrupt the elements that regulate the ErbB family protein expression such as RNA processing. The RNA transcripts of the ErbB family members must be spliced to be functional due to their immense size and the number of introns in these genes. Therefore, any alteration to this process could adversely affect tumor cells. SON, a splicing cofactor, has emerged as a protein of interest in cancer research because of its ability to impact the cell cycle and apoptosis by aiding in pre-mRNA maturation. Based on our preliminary data, we hypothesize that SON is required for ErbB family receptor-driven breast cancer by promoting the expression of not only the ErbB family proteins but also certain ErbB downstream effectors through enhanced RNA splicing. Our studies show that knocking down SON with two independent siRNAs significantly lowers the protein expression of ErbB family proteins ErbB1, ErbB2, and ErbB3 in cancer cells. At the mRNA level, the functional ErbB2 and ErbB3 transcripts decrease because introns are inappropriately retained which causes RNA degradation. These changes lead to a decrease in proliferation and increased apoptosis in breast cancer cells. After examining multiple major signaling pathways with a phospho-kinase array, we found that the activation of several critical ErbB family receptor downstream cascades that respond to stress (p38/JNK) and ensure survival (Akt) are suppressed especially in cells that have high levels of ErbB2. Patient samples were also analyzed which showed that breast tumors tend to have higher levels of SON, and the five year survival for these patients is decreased. Taken together, these data indicate that we have discovered SON as a novel ErbB family receptor splicing factor that may play an important role in breast cancer progression. Our future studies will focus on investigating more in-depth mechanisms by which SON regulates the RNA splicing of the ErbB family and evaluating whether SON can serve as a therapeutic target for breast cancer treatment by using drug and in vivo studies. Citation Format: Joshua Phillips, Jung-Hyun Kim, Sangbin Lim, Erin Ahn, Ming Tan. Regulation of RNA splicing of the ErbB family receptors by the splicing cofactor SON. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1996.