Understanding the role of RAD51AP1 in tumor growth and progression

Abstract

Although much progress has been made in recent years in treatment and prevention, cancer is still the second leading cause of death in the United States. Surgical removal of the tumor is not possible in all cancer types. Therefore, chemotherapy and radiation therapy have become the standard course of treatment and are often the only option for late stage and metastatic tumors. Unfortunately, chemotherapy and radiation therapy resistance are the greatest challenge for physicians trying to eradicate disease, prevent tumor recurrence, and inhibit distant metastasis. This resistance is derived from a heterogeneous population of cells within the tumor known as cancer stem cells (CSCs). CSCs are able to maintain a higher capacity for self-renewal due to an efficient DNA repair system. RAD51-associated protein 1 (RAD51AP1), which is responsible for the successful resolution of double-strand breaks during DNA repair, is overexpressed in wide variety of human cancers. The present study sought to determine the functional role of RAD51AP1 in CSC self-renewal and its relevance to tumor growth and progression and also drug resistance. Our studies provide evidence that RAD51AP1 plays a critical role in CSC self-renewal and maintenance in breast, lung, and colon cancers. To determine the functional role of RAD51AP1 in cancer growth and progression, we generated genetically engineered mouse models in breast, lung, and colon cancer in wild-type Rad51ap1+/+ and knockout Rad51ap1-/- background. In breast and lung cancer models, Rad51ap1 deletion significantly delayed the time of tumor formation and distant metastases, in parallel decreasing the self-renewal capacity of CSCs from each model. Furthermore, to investigate the functional role of RAD51AP1 in colon cancer growth, we utilized AOM/DSS and ApcMin/+ models of colon cancer and found smaller tumor burden along with reduced CSC self-renewal in knockout mice compared to wild-type. Taken together, these data provide evidence that RAD51AP1 plays a critical role in CSC self-renewal in different human cancers and RAD51AP1 could be a novel therapeutic target for cancer prevention and treatment.