Mechanisms of the small nucleolar RNA Snord67 in breast cancer lymphatic metastasis - Project Summary/Abstract Triple-negative breast cancer is an aggressive subtype of breast cancer that tends to metastasize to distant organs early in the course of the disease. Metastasis can occur by cancer cells from the breast tumor directly entering the blood to travel to distant organs (hematogenous metastasis), or by cancer cells spreading from the breast tumor to nearby lymph nodes, and then leaving the lymph nodes to enter the blood and travel to distant organs (lymphatic metastasis). We are interested in understanding how lymphatic metastasis occurs. Cancer cells change their gene expression in order to promote metastasis. One way that cancer cells can regulate gene expression is through the action of noncoding RNAs. We found that the noncoding RNA Snord67 promotes lymphatic metastasis in a mouse model of triple-negative breast cancer. Snord67 is a small nucleolar RNA (snoRNA) that leads to the 2′-O-methylation of another noncoding RNA, U6 small nuclear RNA (snRNA). However, it is unknown whether Snord67 promotes metastasis by increasing the methylation of U6 snRNA or through other, unknown mechanisms. For example, some snoRNAs are known to promote the 2′-O-methylation of protein-coding messenger RNAs (mRNAs), which can lead to changes in mRNA processing, stability, or translation into proteins. The goal of this proposal is to determine whether Snord67 promotes lymphatic metastasis by increasing the methylation of U6 snRNA or by performing other functions, such as increasing the methylation of mRNAs. This proposal includes two aims: (1) Determine the functional importance of Snord67- guided 2′-O-methylation of U6 snRNA at C60 (canonical mechanism) in the promotion of lymphatic metastasis by Snord67, and (2) Determine the contribution of Snord67-guided 2′-O-methylation of target mRNAs (non- canonical mechanism) to the promotion of lymphatic metastasis by Snord67. These studies will help us better understand how triple-negative breast cancer spreads and could potentially lead to new approaches for treating or preventing breast cancer metastasis. The trainee will work in a highly productive multidisciplinary scientific environment and develop proficiency in a variety of experimental methods in RNA biology and cancer biology under the mentorship of physician–scientist experts.
