Members of the Rho, Rac, Ras, and Rap families of small GTPases regulate cancer development and progression. In addition, Ras and other small GTPases can alter the sensitivity of cancer cells to radiation and chemotherapy. Identifying new ways to suppress small GTPase activation in cancers may provide new treatment approaches. While most small GTPases promote cancer and are oncogenic, a few of the small GTPase family members are actually tumor suppressors. Our laboratory studies members of the small GTPase family which have tumor suppressor activities.
The DIRAS family of small GTPases has the unique property of having tumor suppressive actions, rather than the tumor promoting actions common to most other small GTPases. DIRAS1 and DIRAS2 are poorly characterized thus far, with the literature consisting of only a few publications demonstrating tumor suppressor functions in central nervous system and esophageal malignancies. DIRAS3 (ARHI) is the most studied of the DIRAS proteins. DIRAS3 is downregulated or lost in 40-70% of ovarian and breast cancers. Overexpression of DIRAS1 inhibits Ras-mediated cellular transformation of NIH3T3 cells, and DIRAS3 dramatically inhibits cells growth of breast and ovarian cancer cells. Our laboratory is currently studying the roles of DIRAS signaling in breast cancer and other malignancies.
Our long-term goal is to understand how small GTPases can be manipulated to enhance cancer treatment. The knowledge obtained from our studies may help define novel signaling pathways that modulate the functions of pro-oncogenic small GTPases in the Ras family. We hypothesize that knowledge of DIRAS family tumor suppressive signaling can identify new targets for cancer therapeutics and help to identify novel ways in which to abolish pro-oncogenic small GTPase signaling which is critical in the development and progression of a number of malignancies.